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.

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.

Long-term outcome of allogeneic or autologous haemopoietic cell transplantation for acute lymphoblastic leukaemia in second remission in children. GETMON experience 1983-1998.

We present a retrospective study of long-term outcome and predictive factors of survival and relapse in 219 paediatric patients with acute lymphoblastic leukaemia (ALL) in second remission. They received allogeneic (allo) or autologous (auto) haemopoietic cell transplantation (HCT) depending on the availability of a matched sibling donor. The probability of event-free survival (EFS) for the total patient group was 0.35+0.03 at 14 years. No significant differences were observed for EFS between allo- and auto-HCT: 0.39+0.05 vs 0.32+0.04 (P=0.43). A better EFS was seen in patients with a late relapse (LR) (P=0.06 and 0.02, for allogeneic and autologous respectively). Significantly better EFS was observed in allo-HCT patients under 10 years of age and in auto-HCT patients with leukocytes at diagnosis below 25 x 109/l and late relapse. Predictive factors of failure in both groups were early relapse (ER), medullary relapse and age over 10 years. The probability of relapse (RP) for the total group of patients was 0.57+0.03, and it was significantly higher in auto-HCT patients: 0.65+0.04 vs 0.42+0.06 (P=0.002). Factors predictive for relapse were medullary and early relapse, auto-HCT and WBC >25 x 109/l at diagnosis.

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)

Pneumococcal pericarditis with cardiac tamponade in a patient with chronic graft-versus-host disease.

We report a case of pneumococcal pericarditis in a 13-year-old boy following allogeneic BMT from an HLA-identical unrelated donor. The post-transplant course was complicated by chronic GVHD which led to reinstitution of immunosuppressive therapy. Eight months after BMT the patient developed pericarditis with cardiac tamponade, and Streptococcus pneumoniae was isolated in the pericardiocentesis fluid. This is the first reported case of pneumococcal pericarditis after BMT. Although pericardial effusions after allogeneic BMT are often sterile and related to conditioning therapy or associated with chronic GVHD, rapid microbiological investigation and empirical treatment with antibiotics are necessary. Prophylaxis for pneumococcal infection in patients with chronic GVHD is recommended.

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.

Autologous stem cell transplantation for advanced Hodgkin's disease in children. Spanish group for BMT in children (GETMON), Spain.

This study evaluates the outcome of myeloablative chemo-radiotherapy and autologous stem cell transplantation (ASCT) in children with Hodgkin's 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.

Quality of life in young adults having received a BMT during childhood: a GETMON study. Grupo Español de Trasplante de Médula Osea en el Niño.

A quality-of-life questionnaire study was administered in a group of 98 disease-free survivors more than 3 years after BMT. All participants were over the age of 17 years at the time of the survey. The transplants were performed between 1981 and 1993 in eight Spanish hospitals. Eighty-three percent of patients had undergone BMT for neoplastic disease. Seventy-three per cent received an allogeneic bone marrow transplantation. A modified version of a questionnaire applied in Stanford Hospital to evaluate quality of life in adults after BMT was used. A single investigator was responsible for interviewing all subjects by telephone. We compare these results with the same questionnaire applied in a control group of 58 healthy subjects of similar age. The most significant results were: BMT patients valued their quality of life more highly than the control group. The mean score for global quality of life was 8.19+/-0.17 in BMT group as compared to 7.54+/-0.13 in control group (P=0.0013). Studies were cited as the major concern in both groups: 24% in BMT group and in 69% in control group (C.I. 95%=0.59 to 0.30). The patients in the BMT group considered they had fewer problems in comparison with the control group regarding interpersonal relationships with family members and friends, sleep, depression and leisure possibilities. However, they considered they had more problems concerning their physical appearance, studies and work possibilities than their peers. Considerations regarding weight, height, sexual functioning, anxiety, tendency to suffer illness and problems with insurance were similar in both groups.

Translocation (10;11)(p13;p15) in an infant acute myeloid leukemia with MLL gene rearrangement.

Molecular rearrangements of the MLL gene at the 11q23 region have been identified in most cases of infant leukemia, regardless of the phenotype. We present a case of acute myeloid leukemia which coexpressed myeloid and lymphoid markers in a 12-month-old girl. Karyotype analysis revealed the presence of a thus far unreported translocation t(10;11)(p13;p15). Although no 11q23 abnormalities were cytogenetically detectable, an MLL gene molecular rearrangement was found.

Treatment of acute leukemia in children: recent advances and future challenges.

Recently advances have been made in the treatment of acute leukemia in children, it is now possible to cure more than 70% of children with acute lymphoblastic leukemia. With the introduction of more intensive chemotherapy regimens in patients at higher risk of relapse and the identification of cases that could be less intensely treated to diminish long-term toxicity, it could be possible to improve these excellent results. In contrast, pediatric acute myeloid leukaemia seems to be a more heterogeneous disease and its response to conventional chemotherapy is not as uniform. Introduction of new and more efficacious therapies is necessary to improve the poor outcome, especially among patients with high-risk features.

[Prevention of acute graft versus host disease using 3 prophylactic schemes]. / Prevención de la enfermedad injerto contra huésped aguda con tres esquemas profilácticos diferentes.

During 7 years 81 patients received an allogeneic bone marrow transplant (BMT) for several diseases. The prevention of graft-versus-host disease (GVHD) was undertaken with methotrexate (MTX), MTX plus antilymphocytic gammaglobulin plus prednisone (MTX + ALT + P), and elimination of the T-lymphocytes of the donor's bone marrow with the monoclonal antibody CAMPATH-1. The actuarial survival of the patients who did not develop GVHD was significantly better than that of those who developed grade II-IV GVHD: 56% [95% confidence interval (CI) 39-71%] versus 10% (95% CI 3-25%) (p less than 0.0001). However, actuarial survival was similar in each of the three groups: MTX 35%, MTX + ALT + P 38%, and CAMPATH-1 43%. The incidence of GVH disease, when the sex of the donor and the receptor were different, was significantly higher than in cases where the donor and the receptor had the same sex: 45% (95% CI 31-58%) vs 15% (95% CI 8-28%) (p less than 0.005). By contrast, significant differences were not found between the three groups in the incidence of GVHD: MTX 36%, MTX + ALT + P 34%, and CAMPATH-1 20%. In patients with leukemia, a higher number of relapses occurred in the MTX group, because a higher number of patients in second or third complete remission (CR) or with active disease underwent transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Molecular study of red cell pyruvate kinase deficiency in 15 patients with chronic hemolytic anemia. Group of Erythropathology of Hematology and hemotherapy Association of Spain (HHAS)]. / Estudio molecular del déficit de piruvatocinasa eritrocitaria en 15 pacientes con anemia hemolítica crónica. Grupo de Eritropatología de la Asociación Española de Hematología y Hemoterapia (AEHH).

BACKGROUND: Identification of RBC pyruvate-kinase (PK) gene mutations by polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) followed by PK gene sequencing in positive cases has been assessed and the results obtained with a preliminary study of 15 unrelated patients of Spanish origin are presented. PATIENTS AND METHODS: Patients have been classified into two different groups: group 1, propositus (15 cases), and group 2, relatives of the patients included in group 1 (10 males and 5 females). In group 1, a PCR was followed by SSCP and sequencing, and in group 2, the PCR was followed by digestion with specific restriction endonucleases (PCR-ER). RESULTS: Group 1: from 15 patients included in the study 2 were identified as homozygous, 4 as heterozygous and 9 as compound heterozygous. In this group, were identify 26 affected alleles with 11 different mutations: T1456 10 alleles (38.6%), T721 3 alleles (11.6%), A1010, C514, C1015 and T1223 2 alleles (7.7%), and C1070, A1291, T1508, A1595 y T1675 one allele. Relatives from 8 out of 15 patients from group 1 showed the following pattern: homozygous (one case), heterozygous (10 cases), compound heterozygous (2 cases) and normal (2 cases). CONCLUSIONS: SSCP procedure followed by direct gene sequencing in positive cases is fast and simple enough to allow the identification of PK deficient variants, avoiding the need of biochemical characterisation of semipurified deficient enzyme, which is more cumbersome and time consuming. In addition, the PCR-ER method is a very useful tool for screening of the most frequent molecular variants, as well as, for the detection of the carrier condition of this enzymopathy (family studies).

[Prospective study on the prevalence of iron deficiency in Cantabria among children 6 to 14 years old]. / Estudio prospectivo sobre la prevalencia de ferropenia en Cantabria entre niños de seis a catorce años.

Iron deficiency is the most common worldwide micronutrient deficiency in developed countries. To analyze its prevalence in children and adolescent population from our region, we studied Hb, Hto, red cell volumes, serum iron, total iron binding capacity, transferrin saturation and serum ferritin in a population of 380 individuals. These also fulfilled an epidemiological questionnaire. Mean values and normal reference ranges are shown according to age sex, which is very important to optimize the identification of individuals with iron deficiency. Overall prevalence of iron deficiency was 15.7% and it was higher in adolescent males from 12-14 years (21.8%) and children from 6-8 year (18.8%). Significant differences related to residence or to socioeconomic status were not found. The health consequences of iron deficiency are to be considered in any public health planning project.

Fatal meningoencephalitis caused by Scedosporium inflatum (Scedosporium prolificans) in a child with lymphoblastic leukemia.

A fatal case of meningoencephalitis caused by Scedosporium inflatum (Scedosporium prolificans) in a 5-year-old boy with acute myeloblastic leukemia who was given intrathecal treatment is reported. Itraconazole treatment was ineffective. The fungus was identified on brain sections at autopsy and was not observed in any other organ. As no other portal of entry was detected, meningoencephalitis may have originated via direct introduction of the fungus at therapeutic lumbar puncture.

Unusual ultrastructural findings in neuroblastoma.

A morphologic study was made of the cell population which had infiltrated the bone marrow of a five-year-old boy. These cells showed a tendency to form rosette-like structures. These structures as well as the presence (at ultrastructural level) of neurosecretory granules, cell processes, and microtubules in the neoplastic cells led to a diagnosis of neuroblastoma. Certain characteristics, not previously reported in neuroblastoma, were identified, such as gap junction type intercellular contacts, paracrystalline arrays in mitochondrial atpyical cristae and nucleolus-like bodies (nematosomes). Gap junctions are involved in the intercellular transfer of ions and low molecular weight metabolites and may explain the tendency to form cellular cluster in "rosettes" which are characteristic of this neoplasm. The presence of nematosomes in the tumor cell cytoplasm is one more piece of evidence which substantiates the nervous origin of these cells.

[Idiopathic form of late hemorrhagic disease caused by a deficiency of vitamin K. A presentation of 3 cases]. / Forma idiopática de la enfermedad hemorrágica tardía por déficit de vitamina K. Presentación de tres casos.

Three one month old infants with idiopathic late haemorrhagic disease due to vitamin K deficiency are reported. Patients had been exclusively breast fed and had not received vitamin K at birth. Initial symptomatology was typical in the three cases. Two of them had an intracranial haemorrhage with exitus in one of them. Coagulation study showed non measurable levels of PT and PTT and a significant reduction in vitamin K dependent factors. Coagulopathy was corrected with parenteral administration of vitamin K and fresh plasma. Pathogenic factors of this entity are reviewed and present day recommendations to prevent occurrence of this problem are discussed.

[Prognostic value of the changes in the DNA of blast cells from patients with acute lymphoblastic leukemia]. / Importancia pronóstica de las alteraciones en el ADN de las células blásticas en pacientes con leucemia aguda linfoblástica.

The cytogenetic characteristics of 37 patients diagnosed of acute lymphoblastic leukaemia are presented. The studies were performed by cytofluorometry (CFM) after DNA staining with propidium iodide (34 cases) and/or chromosome identification with trypsin G bands (13 patients). Hyperdiploid DNA index was present in 15% of the patients, whereas none of them had hypodiploid DNA index. Abnormal karyotype was found in 69% of the evaluated cases. Good correlation was observed between the ploidy attained by CFM and by karyotyping cells. The highest percentage of aneuploidy corresponded to the L2 morphological subtype (55%), followed by L1 (36%). Structural alterations were the commonest in L2 variant, while numerical ones were commonest in the L1 variant. The 4 L1 patients with aneuploidy had the common immunophenotype, whereas the 6 aneuploidic patients of the L2 variant had common, early pre-B and undifferentiated immunophenotype. The actuarial survival of patients with diploid DNA index was 48.5% (IC 95%, 25-73%), whereas pseudodiploid patients have relapsed and died before 16 months from diagnosis (p less than 0.005). None of the patients with hyperdiploid DNA index and lacking structural alterations has relapsed. Patients with structural abnormalities have the poorest prognosis, while patients with hyperdiploid DNA index showed several favourable risk factors and are in the first complete remission.

Long-term results of high-dose chemotherapy and autologous stem cell rescue for high-risk neuroblastoma patients: a report of the Spanish working party for BMT in children (Getmon).

The authors retrospectively analyzed the long-term outcome of 67 patients over 1 year of age at diagnosis with high-risk neuroblastoma (stage 4 or stage 3 with N-myc amplification) who were treated with megatherapy and stem cell rescue from 1984 to 1998. Median age at transplant was 4 years (range 1.6-15 years). The source of cells was peripheral stem cells in 29 and bone marrow in 38 patients. In 12 patients, an in vitro purging of bone marrow harvest was performed. Most patients were conditioned with melphalan, BCNU, and VM-26. After transplant 19 patients received complementary treatment with IL-2 (16) or 13-cis-retinoic acid (3). Six patients (8%) died from transplant-related toxicity and 39 from disease progression. Three patients were alive with active disease at the time of analysis. Nineteen patients are alive and disease-free at a median follow-up of 104 months. Five-year event-free survival is 0.30. Survival of patients who received a purged graft was not significantly better than the rest. Post-transplant complementary treatment significantly improved overall and event-free survival (p = .01 and p = .04, respectively).