Teresa Olivé

Long-term neuropsychologic sequelae of childhood leukemia: Comparison of two CNS prophylactic regimens

To compare the late neuropsychologic toxicities of CNS prophylaxis in childhood acute lymphoblastic leukemia (ALL), a transversal assessment was performed in two groups of ALL patients and two control groups. The ALL patients had received one of the following CNS prophylaxes: cranial irradiation, 24 Gy and i.t. MTX 10 mg/m2, 6 doses (RT group, n = 25) or i.t. Ara-C 30 mg/m2 and i.t. MTX 10 mg/m2, 10 doses (ChT group, n = 29). The two control groups were: Siblings (Sb, n = 24) and Solid Tumors (ST, n = 22). Intelligence Quotient (IQ), memory, learning, attention and frontal tasks were studied. Comparative analyses between ChT and RT showed no differences in any of the tests. When RT was compared with ST or Sb, RT showed a 10-point lower mean IQ (p greater than 0.05). The results of ChT versus ST or versus Sb were worse in the ChT group. In many tests the differences were statistically significant. Analyses of the 54 ALL patients compared with the 46 controls showed significant differences in all tests except verbal memory and verbal learning. Neuropsychological sequelae of CNS prophylaxis are discussed, and in particular, the role of cranial radiotherapy and i.t. Ara-C. We conclude that prophylactic CNS therapy may cause cognitive dysfunctions.

Feasibility and results of bone marrow transplantation after remission induction and intensification chemotherapy in de novo acute myeloid leukemia. Catalan Group for Bone Marrow Transplantation.

PURPOSE To evaluate prospectively the feasibility and results of bone marrow transplantation (BMT) after induction and intensification chemotherapy (CT) in patients with de novo acute myeloid leukemia (AML). PATIENTS AND METHODS A total of 159 patients less than 51 years of age were treated. Induction CT consisted of daunorubicin 60 mg/m2 for 3 days, cytarabine (ARA-C) 100mg/m2 for 7 days, and etoposide 100 mg/m2 for 3 days. The first intensification therapy included mitoxantrone 10 mg/m2 for 3 days and ARA-C 1.2 g/m2 every 12 hours for 4 days. Amsacrine (100 or 150 mg/m2 for 3 days) and ARA-C (1.2 g/m2 every 12 hours for 2 or 4 days) were given as the second intensification therapy. Depending on the availability of a human leukocyte antigen (HLA)-identical sibling, the intention of treatment after CT was allogeneic BMT (allo-BMT) or autologous BMT (ABMT). RESULTS Complete remission (CR) was obtained in 120 patients (75%) and partial remission (PR) in 11 (7%), while 15 patients (10%) were refractory and 13 (8%) died during induction. There was a trend for better leukemia-free survival (LFS) at 4 years for patients assigned to the ABMT group (50% +/- 6%) compared with the allo-BMT group (31% +/- 7%) (P = .08). This difference in LFS reached statistical significance when considering only transplanted patients (63% +/- 3% at 4 years after ABMT and 38% +/- 11% after allo-BMT, P = .02). The favorable results in patients who received ABMT (no toxic deaths and 37% +/- 7% probability of relapse at 4 years) contrast with the poor outcome of allografted patients (11 patients with transplant-related mortality). CONCLUSION Our study reflects the difficulties in the completion of a therapeutic strategy that include BMT and suggests that intensification before BMT may be useful in the setting of ABMT, but this approach was associated with a high mortality rate in allo-BMT patients.

Role of the intensive care unit in children undergoing bone marrow transplantation with life-threatening complications.

The role of support measures in the Intensive Care Unit for bone marrow transplant recipients has been controversial. Data from 176 pediatric bone marrow transplants were retrospectively analyzed to ascertain the probability, causes, risk factors and survival for life-threatening complications requiring intensive care. Ninety-two patients underwent allogeneic BMT and 84 autologous BMT between January 1991 and December 1995. Thirty-one ICU admissions were recorded. The most frequent causes were acute respiratory failure (n = 15, mostly interstitial pneumopathies), septic shock (n = 5) neurological disorders (n = 5) and heart failure (n = 2). The cumulative incidence of an ICU admission at 20 months post-transplant in patients with an allogeneic BMT was 25.7% (CI: 16.4–35.1), compared with 10.8% (CI: 4.2–17.5) in those with an autologous graft (P = 0.04). ICU admission frequency was maximum during the first 2 months post-transplant. All complications in patients with autologous transplants appeared during the first 5 months post-transplant. Among patients with allogeneic grafts, four were later admitted to the ICU, at 7, 9, 12 and 20 months post-transplant, respectively. The main risk factor for ICU admission was acute GVHD grades III–IV. No differences were found between patients with allogeneic transplants with GVHD grades 0–II and those undergoing autologous transplant. In contrast, differences were highly significant between patients undergoing allogeneic transplants with GVHD grades III–IV and those with GVHD grades 0–II or autologous transplants. No differences were observed between allogeneic and autologous transplants in terms of causes for ICU admission, duration of stay, hours on mechanical ventilation, hours on inotropic drug therapy and numbers of organs failing. Neither were differences found in ICU discharge survival between patients with allogeneic (50%, CI: 29.1–70.9) and autologous (66.7%, CI: 29.9–89.1) transplants. ICU discharge survival in patients admitted for lung disease was 28.6% (CI: 12.1–65.6) but 76.5% (CI: 41.9–87.8) in patients admitted for other causes (P = 0.007). ICU discharge survival in mechanically ventilated patients was 46.2% (CI: 27.0–65.4), significantly lower than non-ventilated patients (100%). Three-year survival in all transplanted patients admitted to the ICU was 29.7% (CI: 13.1–45.0) compared with 70.2% (CI: 62.7–77.6) in patients not requiring ICU admission (P < 0.001). although a complication requiring admission to the icu is, as confirmed by multivariate analysis, an unfavorable factor in long-term survival of transplanted patients, it must be emphasized that three of every 10 patients admitted to the icu were alive and well at 3 years. intensive care support in these patients can be life-saving.

Lentiviral-mediated Genetic Correction of Hematopoietic and Mesenchymal Progenitor Cells From Fanconi Anemia Patients

Previous clinical trials based on the genetic correction of purified CD34(+) cells with gamma-retroviral vectors have demonstrated clinical efficacy in different monogenic diseases, including X-linked severe combined immunodeficiency, adenosine deaminase deficient severe combined immunodeficiency and chronic granulomatous disease. Similar protocols, however, failed to engraft Fanconi anemia (FA) patients with genetically corrected cells. In this study, we first aimed to correlate the hematological status of 27 FA patients with CD34(+) cell values determined in their bone marrow (BM). Strikingly, no correlation between these parameters was observed, although good correlations were obtained when numbers of colony-forming cells (CFCs) were considered. Based on these results, and because purified FA CD34(+) cells might have suboptimal repopulating properties, we investigated the possibility of genetically correcting unselected BM samples from FA patients. Our data show that the lentiviral transduction of unselected FA BM cells mediates an efficient phenotypic correction of hematopoietic progenitor cells and also of CD34(-) mesenchymal stromal cells (MSCs), with a reported role in hematopoietic engraftment. Our results suggest that gene therapy protocols appropriate for the treatment of different monogenic diseases may not be adequate for stem cell diseases like FA. We propose a new approach for the gene therapy of FA based on the rapid transduction of unselected hematopoietic grafts with lentiviral vectors (LVs).Previous clinical trials based on the genetic correction of purified CD34+ cells with γ-retroviral vectors have demonstrated clinical efficacy in different monogenic diseases, including X-linked severe combined immunodeficiency, adenosine deaminase deficient severe combined immunodeficiency and chronic granulomatous disease. Similar protocols, however, failed to engraft Fanconi anemia (FA) patients with genetically corrected cells. In this study, we first aimed to correlate the hematological status of 27 FA patients with CD34+ cell values determined in their bone marrow (BM). Strikingly, no correlation between these parameters was observed, although good correlations were obtained when numbers of colony-forming cells (CFCs) were considered. Based on these results, and because purified FA CD34+ cells might have suboptimal repopulating properties, we investigated the possibility of genetically correcting unselected BM samples from FA patients. Our data show that the lentiviral transduction of unselected FA BM cells mediates an efficient phenotypic correction of hematopoietic progenitor cells and also of CD34- mesenchymal stromal cells (MSCs), with a reported role in hematopoietic engraftment. Our results suggest that gene therapy protocols appropriate for the treatment of different monogenic diseases may not be adequate for stem cell diseases like FA. We propose a new approach for the gene therapy of FA based on the rapid transduction of unselected hematopoietic grafts with lentiviral vectors (LVs).

Unrelated cord blood transplantation for severe combined immunodeficiency and other primary immunodeficiencies

HCT is currently the treatment of choice for children with severe primary immunodeficiencies (PIDs). Frequently, these patients lack an HLA-identical sibling donor, and umbilical cord blood (UCB) transplantation may be an option; however, experience in this field remains scant. Fifteen children with PID (SCID 11, X-linked lymphoproliferative syndrome 2, Omenns syndrome 1, Wiskott–Aldrich syndrome 1) received a UCB transplant. The donor was unrelated in 14 cases and related in 1. Median age at transplant was 11.6 months (range, 2.9–68.0) and median weight 7 kg (range, 4–21). Thirteen patients were conditioned with busulphan and cyclophosphamide and 2 with fludarabine and melphalan. Nine patients received antithymocyte globulin. Median NC × 107/kg infused was 7.9 (range, 2.9–25.0) and median CD34 × 105/kg 2.9 (range, 1.0–7.9). All patients engrafted. Median days to >0.5 × 109/l neutrophils was 31. Eight patients developed acute graft-versus-host disease (GvHD) grades II–IV and one chronic GvHD. Viral and fungal infections were frequent. Four patients died: three from GvHD grade IV complicated by infection and one from progressive interstitial lung disease. Five-year survival was 0.73±0.12. All surviving patients presented complete immunologic reconstitution. No patient is intravenous immunoglobulin (IVIg) replacement therapy-dependent. UCB transplantation is a valid option for children with PID who lack an HLA-identical sibling donor.

High Survival Rate in Infant Acute Leukemia Treated With Early High-Dose Chemotherapy and Stem-Cell Support

PURPOSE Infants with acute leukemia have a poor prognosis when treated with conventional chemotherapy. It is still unknown if stem-cell transplantation (SCT) can improve the outcome of these patients. In the present study, we review our experience with SCT in infant acute leukemia to clarify this issue. PATIENTS AND METHODS We report the results of 26 infants who were submitted to a SCT for acute leukemia. There were 15 cases of acute myeloid leukemia and 10 cases of acute lymphoid leukemia. One patient had a bilineal leukemia. Twenty-two patients were in their first complete response (CR1), three were in their second CR, and one was in relapse. Eight patients were submitted to allogeneic SCT, and 18 underwent autologous SCT. RESULTS With a median follow-up of 67 months, the 5-year overall survival and disease-free survival (DFS) are 64% (SE = 9%) and 63% (SE = 10%), respectively. Autologous and allogeneic SCT offered similar outcome. There was not any transplant-related mortality, and all deaths were caused by relapse in the first 6 months after SCT. In multivariate analysis, the single factor associated with better DFS was an interval between CR1 and SCT of less than 4 months (P: <.025). CONCLUSION SCT is a valid option in the treatment of infant acute leukemia, and it may overcome the high risk of relapse with conventional chemotherapy showing very reduced toxicity. This study suggests that SCT should be performed in CR1 in the early phase of the disease.

Chromosome fragility in patients with Fanconi anaemia: diagnostic implications and clinical impact

Background Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the ‘gold standard’ test for the diagnosis of FA. Objective To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. Methods Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. Results This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. Conclusions This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.

Autologous stem cell transplantation for advanced Hodgkin's disease in children

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkins disease (HD). Twenty children aged 5 to 18 years (median 10.8 years) at diagnosis, with relapsed, refractory or very poor prognosis HD, underwent ASCT in eight hospitals of our country. Status at transplant was: second complete remission (CR2): n = 12; further cr (cr >2): n = 3, partial remission (PR): n = 2, relapse: n = 2 and first CR (CR1): n = 1. Eighteen patients received chemotherapy-based conditioning regimens: cyclophosphamide, carmustine and etoposide (CBV): 11 (55%), carmustine, etoposide, cytarabine and melphalan (BEAM): 5, other: 2; and two patients were conditioned with TBI/Cy. Peripheral blood (PB) was the source of progenitor cells in 12 patients, BM in seven, and BM plus PB, in one. All patients engrafted. One patient died of sepsis and multiorgan failure at day 28 after transplantation. All four patients with measurable disease (PR or relapse) at transplantation attained complete remission. Five patients relapsed 5–34 months after transplant (median: 11 months). Eighteen children remain alive with a median survival time of 40 months. The projected 5-year overall survival and event-free survival (EFS) rates were 0.95 and 0.62. High-dose therapy with stem cell rescue can lead to durable remissions in children with advanced HD. Bone Marrow Transplantation (2000) 25, 31–34.

Teicoplanin pharmacokinetics in pediatric patients

BACKGROUND The incidence of methicillin-resistant Gram-positive bacteria infections in febrile neutropenic children is high. Teicoplanin is an alternative treatment to vancomycin in these patients but few pharmacokinetic studies of teicoplanin in children have been conducted and optimal dosages have not been well-established. OBJECTIVES To assess the pharmacokinetics of teicoplanin in combination with another antibiotic in Gram-positive infections in pediatric patients undergoing bone marrow transplantation and to determine the most appropriate dosage regimen for this type of patient. METHODS We studied 21 patients divided into 2 groups. In Group A (n = 9) the dosage regimen consisted of 3 loading doses of 10 mg/kg at 12-h intervals, followed by a maintenance dosage of 10 mg/kg/day. Group B (n = 12) received the same loading dose and a maintenance dosage of 20 mg/kg/day. Plasma teicoplanin concentrations were monitored in all patients from the second day after the start of treatment and periodically thereafter. Serum concentrations above 10 mg/l were established as desirable trough values. RESULTS In Group A trough values > 10 mg/l were not reached in five patients and treatment was modified owing to persistent fever. In Group B all patients attained trough values > 10 mg/l. Tolerance to treatment was excellent. CONCLUSION In febrile neutropenic pediatric patients undergoing bone marrow transplantation, maintenance dosages of teicoplanin between 15 and 20 mg/kg/day assure serum concentrations above 10 mg/l. Dosages of 10 mg/kg/day do not assure serum through values above 10 mg/l.

Secondary malignancies and quality of life after stem cell transplantation.

Summary:Malignant diseases (MD) occurring after stem cell transplantation (SCT) are of particular concern as increasing number of patients survive and remain free of their original disease. The cumulative incidence at 15 years is 10–12%. The B-cell proliferative disorders (BCLP) are the most common MD in the first year after SCT; the incidence probability is 1% in allogeneic transplants but is much higher (until 14%) after HLA-identical, T-cell-depleted SCT in which Campath 1G or ATG are given. BCLP develop because of reactivation of the EBV and a depressed cellular immunity. Prediction of risk of BCLP can be made by frequent monitoring of EBV load in patients with risk factors. The most effective therapies are the early administration of anti-CD20 monoclonal antibody and adoptive immunotherapy with in vitro generated EBV-specific cytotoxic T cells. Myelodysplasia and acute myeloid leukemia with very poor prognosis have been described in 4–18% of patients with non-Hodgkin lymphoma and Hodgkin disease, 12–24 months after autologous SCT. The risk of development of solid tumors increases over time and the cumulative incidence among children who underwent an SCT at less than 10 years of age is 6–11% at 15 years. There are few studies evaluating quality of life (QOL) in children and adolescents who had received an SCT. The findings of these studies can be summarized as follows: (a) The majority of long survivors enjoy good QOL and return successfully to school or work. (b) A minority (10–15%) complain of physical problems or present moderate cognitive or psychological dysfunctions. (c) The importance of family, other social support and psychological adjustments is generally recognized. More extensive, longitudinal and comparative studies with other alternative therapies are required.