Long-term outcome and prognostic factors of unrelated cord blood transplantation in children with haematological malignancies: a retrospective study using the Spanish Working Party for BMT in Children (GETMON) database.

Outcomes of unrelated cord blood transplants (UCBT) were assessed in 172 consecutive children, median age 5 years (range: 0.5-18), with haematological malignancies treated at nine Spanish hospitals between February 1996 and April 2009. Data were collected from the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) database. ALL was diagnosed in 125 patients, AML in 43 and myelodysplastic syndrome in 4. Myeloid engraftment (ANC⩾0.5 × 10(9)/L) occurred in 87.2% at a median of 22 days and was associated with the total nucleated cell (TNC) dose infused and use of a TT-containing conditioning regimen. Cumulative incidence of relapse was 20% at 1 year post transplant and 29% at 3 years, being higher in patients with a diagnosis of ALL, very high risk disease and GVHD grades 0-1. Cumulative incidence of non-relapse mortality (NRM) was 19% at 100 days post transplant and 39% at 1 year. BU-FLU-TT-ATG-conditioned patients had lower NRM. Disease-free survival (DFS) was 40% at 2 years post transplant (for patients transplanted since 2006). On multivariate analysis, TNC dose infused, AML and BU-FLU-TT-ATG-conditioning regimen increased the probability of DFS. It is of paramount importance to select cord blood units with the highest cell dose. As the BU-FLU-TT-ATG-conditioning regimen was associated with better DFS owing to lower NRM, further prospective studies testing this regimen are warranted.

Allogeneic hemopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon).

The authors report the results of 58 children with ALL in 2CR after related (n = 31) or unrelated (n = 27) AHSCT. Characteristics at diagnosis and initial and after relapse antileukemic treatment were similar in the related donor (RD) and the unrelated donor (UD) groups. Conditioning consisted of TBI/CY +/- VP-16 for patients > or = 3 years old (n = 43) and Bu/CY for the rest. Median recipient age was 8 years (range 1-17) in the RD and 9 years (range 3-14) in the UD group. Median follow-up was 54 months (range 24-80) and 52 months (range 22-85) in the RD and the UD groups repectively. The 5-year EFS probability was 43 +/- 9% for the RD group and 36 +/- 9% in the UD group (p = .25). The transplant-related mortality was 16% in the RD and 37% in the UD group (p = .016). In the RD group 36.7% of patients relapsed versus 18.6% in the UD group (p = .05). GvHD associated with organ failure or infection caused most of the transplant-related deaths in both groups. Survivor quality of life for both groups was good (Lansky score < or = 90).

Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON).

Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome. The authors retrospectively analyzed the outcome with this procedure in 13 patients with severe Wiskott-Aldrich syndrome transplanted in 5 Spanish centers from 1989 to 2006. A patient was transplanted twice from the same donor due to a late engraftment failure. Age at transplant ranged from 7 to 192 months (median 30 months). There were 10 matched donors (3 related and 7 unrelated), 2 mismatched unrelated, and 1 haploidentical. Conditioning regimen consisted of busulfan and cyclophosphamide (BuCy) in 11 cases and fludarabine and melfalan (1) or BuCy (1). ATG was added in transplants from non-genetically matched donors. GvHD prophylaxis consisted of cyclosporine and methotrexate in most patients plus T-cell depletion in the haploidentical HSCT. Nine of the 13 transplanted patients are alive with complete clinical, immunologic, and hematologic recovery 8-204 months (median 101 months) after HSCT. Eight surviving patients had been transplanted from matched donors (3 related and 5 unrelated) and 1 from a haploidentical donor. Four patients died, 2 transplanted from matched donors (1 from acute GvHD and organ failure, 1 from a lymphoproliferative disorder after a second transplant), and 2 transplanted from mismatched unrelated donors (1 from acute GvHD and organ failure, 1 from graft failure and infection). Allogeneic hemopoietic stem cell transplantation must be utilized in all patients with severe Wisckott-Aldrich syndrome, using the most suitable graft variant for each patient.

Matched-pair analysis comparing allogeneic PBPCT and BMT from HLA-identical relatives in childhood acute lymphoblastic leukemia.

This multicenter study was designed to evaluate whether allo-PBPCT provides some advantages, if any, over BMT in terms of engraftment kinetics, acute and chronic GVHD incidence, TRM, relapse incidence and survival in acute lymphoblastic leukemia patients (ALL). From January 1995 to December 1999, 67 ALL patients (34 in the PBPCT group and 33 in the BMT group) were included in this study. Median age for both groups was 8 years (range, 1-18). There were 24 patients in first or second CR in the PBPCT group and 28 such patients in the BMT group. Preparatory regimens were TBI-based in 26/34 in the PBPC group and 25/33 in the BMT group. GVHD prophylaxis was CsA alone in 38 patients (18 PBPCT vs 20 BMT) and CsA plus short Mtx in 29 (16 PBPCT vs 13 BMT). Engraftment was achieved in all cases. Median days to neutrophil recovery was 10 (range, 7-18) after PBPCT vs 14 (range, 9-21) after BMT (P < 0.0001). Platelet engraftment (>50 x 10(9)/l) was also faster for PBPCT patients (median 13 days, range, 9-40 vs 23 days, range, 15-165) (P < 0.0001). Acute GVHD grade II-IV incidence was similar in both groups (46.4 +/- 8.8% vs 42.7 +/- 8.6%) (P = 0.45). Probability of chronic GVHD was 50.6 +/- 12.2% after PBPCT vs 27.8 +/- 9.2% after BMT (P = 0.1). Probability of relapse was similar (28.7 +/- 9.2% for PBPCT vs 27.1 +/- 8.2% for BMT) (P = 0.89). There were eight patients who died from transplant-related complications after PBPCT vs 5 after BMT (P, NS). With a median follow-up of 25 months the event-free survival probability was 53 +/- 8.9% for PBPCT vs 54.9 +/- 9.7% for BMT (P = 0.54). Using PBPC for allogeneic transplantation in childhood ALL results in faster hematopoietic recovery compared to BM, with a similar incidence of aGVHD, TRM, relapse and disease-free survival. However, the issue of cGVHD remains unresolved.

High survival rate in infant acute leukemia treated with early high-dose chemotherapy and stem-cell support. Groupo Español de Trasplante de Médula Osea en Niños.

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.

[Reconstitution of peripheral blood lymphocytes in patients treated with bone marrow transplantation: comparison between allogeneic and autologous transplantation]. / Reconstitución de los linfocitos de sangre periférica en pacientes tratados con trasplante de médula ósea: comparación entre el trasplante alogénico y el autólogo.

BACKGROUND: This study compares the immune reconstitution of total T cells, CD4 and CD8 cell subsets, activated T cells, NK cells and B cells in 66 patients who underwent allogeneic or autologous bone marrow transplantation (BMT). PATIENTS, MATERIAL AND METHODS: The reconstitution of peripheral lymphocytes subsets was studied using two-color flow cytometry. The study group consisted of 39 patients who received allogeneic BMT compared with 27 patients who received autologous BMT. Peripheral blood was examined at different time intervals. As a measure of immune function, the response to the mitogen phytohemaglutinin (PHA) was determined. RESULTS: The pattern of recovery of CD3+, CD4+ and CD8+ T cells, as well as the PHA response, was similar for each type of transplant. CD3+CD5- cells were significantly higher following autologous BMT than after allogeneic BMT and during more time. An overexpression of DR on T cells following autologous or allogeneic BMT demonstrates an increasing degree of T-lymphocyte activation. This activated T-cell subset was more stable in patients transplanted with allogeneic BM than in patients treated with autologous BM. The levels of total B cells and CD19+CD5+ B-cells were increased during 2 to 12 months following autologous MBT, remaining normal afterwards; in contrast, the levels of CD19+ lymphocytes and CD19+CD5+B-cells remained higher than normal ranges until 36 months in patients transplanted with allogeneic BM. The percentage of NK cells was significantly increased following both autologous and allogeneic BMT. The highest percentage of NK cells were detected about 2 and 6 months post-transplant in patients treated with autologous or allogeneic BM, respectively. CONCLUSIONS: Allogeneic BMT appears to induce a slight delay recovery of B and NK cells in comparison to autologous BMT. In contrast, T-cells recovery was similar for each type of transplant, although a higher percentage of CD3+CD5- T cells and a faster recovery of activated CD3+DR+ cells to normal levels were observed in patients transplanted with autologous BM.

Treatment of Ph1-positive chronic myelogenous leukemia in children: comparison between allogeneic bone marrow transplantation and conventional chemotherapy. Spanish Working Party for BMT in Children (GETMON).

BACKGROUND AND OBJECTIVE: To compare the estimated survival and disease-free survival between children with Ph1-positive chronic myeloid leukemia treated with allogeneic bone marrow transplantation or conventional chemotherapy. DESIGN AND METHODS: In this retrospective study we compared the results obtained in a group of 14 children who received allogeneic bone marrow transplantation (BMT) between 1983 and 1993, and another group of 27 children treated with busulfan, hydroxyurea or alpha-interferon during the same time period. Patients were transplanted at a median of 7 months from diagnosis and all except one were in their first chronic phase. Conditioning consisted in total body irradiation and cyclophosphamide in 12 cases, and busulfan was added in two. RESULTS: Of the 14 patients treated with BMT, two died of transplant-related complications and two relapsed 18 and 48 months after the BMT. Ten children remain alive and disease free at a median follow up of 60 months. The probability of DFS at 5 years is 70%. Of the 27 patients treated with chemotherapy, 22 have died at a median of 36 months from diagnosis. The probability of survival at 5 years is 5% versus 83% for the BMT group (p = 0.001). INTERPRETATION AND CONCLUSIONS: Allogeneic BMT is a safe and very effective treatment for Ph-positive CML in children. Patients who have an HLA-identical sibling donor must receive a transplant as soon as possible after being diagnosed.

Recombinant human erythropoietin (rh-Epo) administration to normal child bone marrow donors.

We have evaluated the efficacy of administering recombinant human erythropoietin (rh-Epo) to 11 healthy bone marrow donors weighing less than 30 kg. Three weeks before harvesting, the donors received 100 units/kg/day rh-Epo subcutaneously and oral iron supplementation (2.5 mg/kg twice daily). Six children with hematocrit values below the normal ranges for their ages after bone marrow harvesting received 150 units/kg rh-Epo three times a week for 2 weeks and oral iron supplementation at the same dose. No rh-Epo side-effects were observed. Hematocrit values before harvesting increased to between 5.7 and 18.5 (mean 10.6 +/- 1.2) above the baseline values (P = 0.0001). Hematocrit after harvesting decreased to between 4 and 19.5% (mean, 11.1) below the day 0 pre-harvest values. On day + 15 all but one patient had a hematocrit value > or = baseline value. No patient required transfusion during or after bone marrow harvest. Our results show that rh-Epo administration can avoid transfusion and has no side-effects in low weight child bone marrow donors.

Megatherapy in children with high-risk Ewing's sarcoma in first complete remission.

To improve the prognosis of patients with metastatic or high-risk localized sarcoma in first CR, we explored the role of consolidation therapy with megatherapy and hematopoietic rescue. From 1986 to 1995, of 72 patients with Ewing's sarcoma from three pediatric departments, 30 were diagnosed as high-risk patients. Of these 30 patients, six did not achieve complete remission and four refused megatherapy and received multimodal treatment (chemotherapy + surgery and/or radiotherapy). The remaining 20 patients received megatherapy. There were 15 males and five females with a median age of 10.8 years (range 2-18 years). Five patients had metastatic disease at initial diagnosis, nine patients had primary tumor in the pelvis and 13 had a tumor volume greater than 100 ml. Overall disease-free survival was 62.7+/-11%; 40+/-21.9% for those with metastatic disease, 76.2+/-12.2% for those with tumor volume greater than 100 ml and 64.8+/-16.5% for those with tumor in pelvic bones. In conclusion, megatherapy has improved the outcome of this group of patients relative to that expected following conventional therapy.

Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission. Spanish Working Party for BMT in Children.

The purpose of this study was to evaluate the outcome of children with acute lymphoid leukemia (ALL) in second remission who have undergone high-dose chemotherapy and radiotherapy and autologous bone marrow transplantation (ABMT) with monoclonal antibody purged marrow, and to determine the main prognostic factors. From 1987 to 1992, 55 children with ALL in second remission underwent ABMT. The conditioning regimen consisted of total body irradiation (TBI) plus cyclophosphamide in 21 patients and TBI plus cyclophosphamide plus cytarabine or VP-16 in 28 patients; the remaining six patients were treated with chemotherapy alone (cyclophosphamide and busulfan, and/or VP-16). The marrow was purged using monoclonal antibodies and complement or magnetic microspheres in all cases. All patients engrafted. Three patients (5%) died early post transplant from infections. Twenty-six patients (47%) relapsed (median 150 days); 26 patients (47%) are alive and in complete remission (CR) at a median of 36 months. The Kaplan-Meier estimation showed a probability of event-free survival (EFS) of 46 +/- 0.007%. In the univariate analysis, first CR length and conditioning with TBI plus two or more cytotoxic drugs were found to be the most significant predictors of EFS. ABMT with purged marrow is a treatment modality which offers a chance of cure in children with ALL after relapse, including children who relapse early.

[Low grade disseminated astrocytoma in childhood]. / Astrocitomas de bajo grado diseminados en la infancia.

INTRODUCTION: Leptomeningeal dissemination is a common event in some kinds of cerebral tumours, but in low-grade astrocytomas who classically have been conferred a benign course. However, multifocal affectation is described each time more frequently in these group of tumours. CLINIC CASES: We present three patients aged respectively 8 and 10 months and 10 years, who were diagnosed of low-grade astrocytoma with multicentric spread. They were treated with systemic chemotherapy and controlled with MRI. At the end of the treatment an important reduction in tumours' size was observed in the three cases. DISCUSSION: Biological behaviour of low-grade astrocytoma as been reviewed in last years. By one side, it has been seen that certain histological characteristics are associated with an aggressive behaviour: on the other hand, long-term evolution of these tumours can be complicated with tumoral recurrence, malignization and leptomeningeal dissemination. This last one is observed each time more frequently since the use of MRI in the diagnose of cerebral tumours has become routine. From the therapeutic point of view, chemotherapy represents an effective choice for these patients' management, when surgery is not possible and radiotherapy not advisable, allowing in many cases to stop tumoral growth and sometimes to reduce it's size strongly.

Bone marrow transplantation in chronic granulomatous disease.

UNLABELLED: We present a 5-year-old boy with a severe form of X-linked chronic granulomatous disease and hypersensitivity to sulphamides preventing prophylaxis with trimethoprim-sulphomethoxazole. Bone marrow transplantation was performed after preconditioning with busulphan and cyclophosphamide. The immediate post-transplant period was without complications. Complete chimerism was demonstrated and post-transplant oxidative metabolism was normal. The patient is asymptomatic 30 months after the graft. CONCLUSION: Bone marrow transplantation in cases of chronic granulomatous disease is controversial, although it could be useful in selected very severe cases in which prophylactic therapy is problematic.

[Allogenic bone marrow transplantation versus autograft in acute lymphoblastic leukemia, in second remission in 113 children. Results of the Grupo Español de Transplante de Medula Niños (GETMON)]. / Trasplante alogénico de medula ósea versus autotrasplante en la leucemia aguda linfoblástica en segunda remisión en 113 niños. Resultados del Grupo Espñol de Transplante de Medula Niños (GETMON).

PURPOSE: Using the data from the GETMON ("Grupo Español de Trasplante de Medula Osea en Niños") we carried out a retrospective analysis of the results of allogeneic bone marrow transplantation (alloBMT) compared to autologous bone marrow transplantation (ABMT) in 113 paediatric patients with acute lymphoblastic leukaemia (ALL) in second remission. Transplants were performed by the following centers, from April 1983 to December 1991: H. Vall d'Hebrón and H. Sant Pau from Barcelona, H. Ramón y Cajal and H. Niño Jesús from Madrid and H. Marqués de Valdecilla from Santander. PATIENTS AND METHODS: The study included 113 patients between the ages of two and 16 years with ALL in second remission at marrow transplant. Fifty-six underwent alloBMT and 57 ABMT. Both groups were homogeneous with respect to age, sex, immunophenotype, duration of first remission, risk at diagnosis, percentage of early and late relapses, percentage with marrow or extramedullary relapse prior to transplant, time interval from attainment of second remission to transplant, and conditioning regimens applied for marrow transplant, with predominance of chemoradiotherapy in both. RESULTS: Haematologic recovery was observed to be faster in alloBMT than in ABMT. A granulocyte count > 0.5 x 10(9)/l was reached in alloBMT patients in a median of 19 days and in ABMT patients in a median of 25 days (p < 0.001). Early procedure-related death after ABMT occurred only in one patient (1.75%) and was caused by hepatic veno-occlusive disease. In the alloBMT group, the incidence was 25%. GVHD and infection were the most common causes. Actuarial DFS for alloBMT was 38.8 +/- 6.7% at 8.5 years versus 29.2 +/- 6.5% at 4.5 years for ABMT, p = NS. No significant differences of actuarial DFS were found between alloBMT or ABMT in patients according to leukocyte count and risk at diagnosis, neither with first remission duration, nor with remission duration at transplant. A separate analysis of actuarial DFS for each group shows that in ABMT group DFS was significantly greater in patients who had presented a late relapse (> 30 months) 61.1 +/- 13.8%, than those who had presented an early relapse (< 30 months) 18.3 +/- 6.5% (p < 0.005). Probability of relapse was significantly greater in ABMT (70%) compared to alloBMT (46%) (p < 0.025). Transplant offers a better DFS in extramedullary relapses compared to isolated or combined bone marrow relapses: 71.4 +/- 17.1% with alloBMT and 38.1 +/- 14.7% with ABMT (p = NS). CONCLUSIONS: In our experience we observed a better DFS with alloBMT compared with ABMT, overcoat in early relapses, but without significant difference. A higher relapse rate in ABMT group is partially compensated by more early deaths in alloBMT offers a few survival possibilities in patients with medullary relapses whose first remission lasted less than 30 months.

[Immunologic reconstitution of peripheral blood lymphocytes in patients treated by bone marrow transplantation]. / Reconstitución inmunológica de los linfocitos de sangre periférica en pacientes tratados con trasplante de médula ósea.

BACKGROUND: Lymphocyte subset reconstitution was studied in 65 patients undergoing allogeneic and autologus bone marrow transplantation (BMT). PATIENTS AND METHODS: The expression of molecules on the membrane of lymphocyte subsets was assessed by two-colour flow cytometry and a direct immunofluorescence assay. The functional capacity of the patient's T lymphocytes following transplantation was identified by stimulation whit peripheral blood lymphocytes; B cells from BMT recipients were tested for their ability to respond, in vitro, to pokeweed (PWD) mitogen. RESULTS: 1) The proportion of CD8+ T lymphocytes was higher than the CD4+ T lymphocytes until 1 1/2 year after-BMT, with high percentage of immature T cells (CD3+, CD8+, HLA-DR+, CD25-) in the first nine months post-transplant. Moreover, a large proportion of T lymphocytes lacked CD5 expression in the first year following BMT. 2) T-cell proliferative response to PHA was low with subsequent recovery until normality. 3) Low numbers of B cells in the first two months with a significant increase since then until 1 1/2 year after-BMT; the phenotype of these B cells was mainly CD19+, CD5+. 4) High in vitro spontaneous immunoglobulin production by peripheral blood B lymphocytes and an impaired response to PWM was observed. 5) Increased percentage of cells with natural killer (CD56) cell phenotype was seen during the 2nd and 3rd months after the graft infusion. After 1 1/2 year postgrafting, this percentage returned to normal level. CONCLUSIONS: Taken together, these data indicate the existence of numerous abnormalities in several subsets of peripheral blood lymphocytes after BMT and suggest a slow kinetics of immune recovery after human marrow transplantation being complete between 18 and 24 months following BMT.

Bone marrow transplantation in 46 pediatric patients with non-Hodgkin's lymphoma. Spanish Working Party for Bone Marrow Transplantation in Children.

We report a retrospective analysis on 46 pediatric patients (median age 9 years, range 1-17 years) with non-Hodgkin's lymphoma (NHL), transplanted in six Spanish centers. Fourteen patients underwent allogeneic bone marrow transplantation (BMT) and 32 autologous BMT. Most patients were boys (36 of 46). Twenty one cases were of lymphoblastic lymphoma, 19 Burkitt's lymphoma and six diffuse large cell lymphoma. Maximal Murphy's stage any time before BMT was stage III in 17 cases and stage IV in 29 cases. At BMT, 13 cases were in first CR, 21 in second CR, seven in third CR, four with sensitive active disease and one with refractory disease. All patients transplanted in CRl were considered candidates for BMT because of delayed CR (two cases), failure of the first-line therapy (seven cases) or central nervous system (CNS) or BM infiltration at diagnosis (four cases). Conditioning therapy included TBI in 33 patients and 13 cases were conditioned with chemotherapy alone. Toxic mortality was 13% (three of 14 in the allogeneic BMT group and three of 32 in the autologous group). No toxic deaths were registered in 13 patients undergoing BMT in CR1 (three allogeneic BMT and ten autologous BMT). Twelve patients relapsed 1-7 months after BMT. Overall event-free survival (EFS) was 58% (42-73%; confidence interval (CI) 95%), with a median follow-up of 33 months. EFS was similar for allogeneic BMT and autologous patients. Disease status at BMT was the only predictive factor for EFS (P < 0.01). There were no significant differences between patients in CR1 (82.5%) and CR2 (68%).(ABSTRACT TRUNCATED AT 250 WORDS)