Indications For Bone Marrow Transplantation Research Articles

Development of Bone Marrow Transplantation Strategies

The use of alternative stem cell sources, the growth of supportive healthcare facilities, and the expansion of indications for bone marrow transplantation (BMT) as well as partially matched donors from the same family are all continuing evolutionary trends as the use of BMT has been developed and expanded to include donors who are not related by blood but have Partial histocompatibility antigen compatibility. Although the outcomes of these transplants are not as good as those performed with first-degree siblings, patients with leukemia, aplastic anemia, and immunodeficiency disorders who cannot receive treatment otherwise they can receive it now. Patients suffering from diseases such as acute myeloid leukemia, acute lymphoblastic leukemia, and Hodgkin lymphoma also show success with autologous bone marrow transplants. Furthermore, bone marrow or blood stem cell support is used after intensive chemotherapy. Patients with stage II, III, and IV breast cancer can benefit from treatment with bone marrow cells found in peripheral blood. In this review, the most important developments in autologous and allogeneic bone marrow transplantation, the control of infectious diseases, and the use of gene therapy to alter genetic disorders that are transmitted from parents to their offspring through bone marrow or peripheral blood infusions are outlined.

Next Generation Sequencing and Cytogenetics in Acute Myeloid Leukemia - Therapeutic and Prognostic Impact: A Retrospective Cohort from a Private Centre of Reference in Latin America

Introduction: Acute Myeloid Leukemia (AML) is a prevalent and severe hematological disorder. The emergence of Next-Generation Sequencing (NGS) and karyotiping, has demonstrated associations between chromosomal abnormalities and mutations with worse treatment response and mortality in AML. Current classification of AML is based on its cytogenetic and molecular profile, as defined by World Health Organization (WHO) 2022 and European Leukemia Net (ELN) 2022. Despite its evident importance in AML, application of these diagnostic methods poses new challenges. In Latin America, particularly, there is a clear limitation of data and studies regarding molecular and cytogenetic analysis in AML patients, due to the relatively short time these techniques have been employed and the few accredited centers able to perform them. Therefore, this study primarily aims to provide an in-depth evaluation of the application of NGS and cytogenetic analysis in AML, identifying the impact of somatic mutations on AML mortality and progression free-survival based on the experience of a reference center in Latin America. Secondarily, we aim to determine the molecular and cytogenetic profile of these population and analyze the impact of age, sex and comorbidities in AML prognosis. Methods: This is an unicentric, retrospective and non-interventional cohort performed in Brazilian Hospital Albert Einstein. Inclusion criteria were adult patients (aged ≥18 years) diagnosed with AML between May 2017 and August 2022, who underwent myeloid panel testing through NGS and cytogenetic evaluation at diagnosis. Independent variables analyzed were age, gender, prognostic risk according to ELN 2022, indication of bone marrow transplantation and molecular and cytogenetic risk at diagnosis. High cytogenetic risk was defined by the presence of at least one of the high-risk karyotype abnormalities described in ELN 2022 and high-risk NGS was defined by mutation in the genes ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, U2AF1, ZRSR2, TP53 or FLT3. The primary outcomes evaluated were overall survival (OS) and progression-free-survival (PFS), estimated by the Kaplan-Meier method. Secondary outcomes were disease relapse and non-relapse-related mortality (NRM). Results: From a total of 168 selected patients, 64 filled out elegibility criteria and were included in the study. Mean age at diagnosis was 62,7 years old with a equal proportion of both sexes. 7 patients (10,9%) were classified as favourable risk according to ELN 2022, 13 (20,3%) as intermediate risk and 44 (68,8%) as high risk. 42 (65,6%) had a standard-risk karyotype, whereas high-risk karyotype was found in 22 (34,4%) patients. 47 (73,4%) individuals presented high-risk NGS mutations, with a higher prevalence of gene rearrangements in RUNX1 (20,1%), FLT3 (18,7%), TP53 (15,6%) and SRSF2 (15,6%). Only 17 (26,6%) patients reported exclusively standard-risk or no mutations. After a median follow-up was 26 months, estimated OS was 73% in 1 year and 54% in 2 years. 1 and 2 years PFS was 63% and 45%, respectively. 11% relapsed after 1 year and 27% after 2 years. The incidence of NRM was 25% and 28% after 1 and 2 years, respectively. High-risk karyotype was associated with a signficant reduction in overall survival (hazard ratio [HR] 2,27, 95% CI 1,09-4,70; p=0·028) and progression-free-survival (HR 2,15, 95% CI 1,23-4,11; p=0·02). On the other hand, there was no statistically significant association between high molecular risk by NGS and OS (HR 1.45, 95% CI 0.59-3.58; p=0.41) or PFS (HR 1.43, 95% CI 0.65-3.13; p=0.37). Progressive age has discreetly impacted in OS (HR 1,05, 95% CI 1,02-1,08; p=00005), PFS (HR 1,03, 95% CI 1-1,05; p=0,025) and NRM (HR 1,06, 95% CI 1,02-1,11; p=0,002). No differences in outcomes were found between sex, ELN 2022 risk groups, and treatment with bone marrow transplantation. Conclusions: Next-Generation Sequencing, combined with cytogenetic analysis, has improved precision in prognosis prediction of AML patients of each patient, allowing safe implementation of appropriate individualized therapy. This study showed and association between high-risk cytogenetics and worse prognosis in AML, but no association was observed between molecular risk and AML morbimortality. Further studies with a bigger population and longer follow-up should be conducted in Latin America in order to better clarify and delve deeper into the results reported in this cohort.

Real World Data Venetoclax Based Therapies in a Single Center in Latin America

Introduction: Venetoclax-based therapies have changed the outcomes of acute myeloid leukemia, in combination with hypomethylating agents, low-dose cytarabine or in older patients not eligible for intensive regimens. Combinations with venetoclax with target therapy and with standard chemotherapy are being tested to improve outcomes in specific subgroups. In Latin America, the lack of clinical trials increases prescriptions not yet approved in international guidelines (off-label use). In this paper, we present data from a private reference center in Latin America for the treatment of acute myeloid leukemia and high-risk myelodysplasia. Methods: This is a unicentric, retrospective, and non-interventional cohort study performed at Brazilian Hospital Albert Einstein. Inclusion criteria were adult patients (aged ≥18 years) diagnosed with AML between May 2019 and January 2023, who were treated with a venetoclax-based regimen. Independent variables analyzed were age, gender, prognostic risk according to ELN 2022, indication of bone marrow transplantation, and molecular and cytogenetic risk at diagnosis. Results: Sixty-three (N= 63) patients were included, with a median age of 63.1 years old. Forty-eight patients received a combination of venetoclax and a hypomethylating agent, two were associated with low doses of cytarabine, eight were associated with target therapy (inhibitor of FLT3), and five with intensive chemotherapy. The median follow-up was 303 days, and the median use of venetoclax in those who did not suspend treatment was 352 days. The main cause of suspension was hematological toxicity. In the univariate analysis, the following onco-hematological karyotype variables, age, type of regimen combined with venetoclax, and decision for transplant did not show statistical significance. Conclusion: Real-world data show that venetoclax-based therapies are effective in patients with AML, and their combinations have been increasingly explored.

NIH Bayesian Score As a Stratification Tool in Sickle Cell Disease - Results from a Single Center Cohort in Brazil

▪Background: Adults with SCD are notoriously difficult to classify into prognostic index of mortality. Our objective was to test the ability of the NIH Bayesian severity score to predict the risk of death in a cohort of patients with SCD followed at a Sickle Cell Outpatient Clinic of the Clinics Hospital, University of Sao Paulo Medical School. Methods: Since 1992 we have been following adult patients with SCD in our outpatient clinic. Data from patients with a follow-up of at least 2 years was collected. When patients completed 2 years of follow-up, data for applying the NIH Bayesian score, available online (http://bios.ugr.es/dss-calculator/) were acquired. The calculator generates a score ranging from 0 to 1, and patients were followed-up until 2016. Patients with more than three missing information were excluded. Survival analysis was performed by means of Kaplan-Meier curves, divided according to quartiles of the different score levels; the log rank test was used for curve comparison. Results: We analyzed 547 records and 219 were excluded due to missing data, leaving 328 patients for analysis. Mean follow-up period was 6.8 years (ranging from 2 to 25 years). We divided the patients into SS/Sβ0-thalassemia (243 patients) and SC patients (85 patients). During this period, 64 patients died (53 in the SS/Sβ0 group, 11 in the SC group). Patients in the group of the higher score (> 0.72) had higher mortality (p= 0.009; Figure 1) . Among SS/Sβ0 patients that died during follow-up, 58% had a score > 0.72, and among SC patients, only 18.2% had this score. Discussion and conclusions: This is the first external validation of the NIH Bayesian score with mortality evaluation. We were able to identify a high mortality risk group (score> 0.72), especially after 5 years of follow-up. In our study, the performance of the score was better to predict risk of death in the SS/Sβ0 group than in the SC group. This study has limitations due to its retrospective nature and the missing information. There is a need for prospective studies to reinforce these findings, but the NIH Bayesian score model for evaluation of SCD severity may help in treatment decision-making, including the indication of bone marrow transplantation especially in SS/Sβ0-thalassemia patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical and Molecular Analysis of Children with Wiskott-Aldrich Syndrome to indicate Bone Marrow Transplantation

Wiskott-Aldrich Syndrome (WAS) is a genetic disease linked to the X chromosome, characterized by recurrent infections, autoimmunity, malignancy, eczema and hemorrhage. Mutations in the WAS gene alter the coding of the WASp protein, expressed mainly in the cytoplasm of hematopoietic cells, with functions of actin polymerization, signaling events and cytoskeletal rearrangement. According to severity, there are four phenotypes described: classical form (WAS), X-linked thrombocytopenia (XLT), X-linked intermittent thrombocytopenia (IXLT) and X-linked neutropenia (XLN). Only the mutation analysis was shown to be of limited value in predicting the clinical phenotype. However, the analysis of protein expression in lymphocytes has been very successful in predicting this phenotype. On the other hand, it is not yet known which patients with XLT phenotype may progress to the classical form and for this reason there are controversies about the indication of bone marrow transplantation in these patients.This study aims to perform a clinical, laboratory and molecular analysis of pediatric patients diagnosed with WAS under our clinical follow-up at Hospital das Clínicas of UNICAMP and follow-up patients at other Brazilian Reference Centers of Primary Immunodeficiency.

Sobrevida e evolução leucêmica de portadores de síndromes mielodisplásicas

As síndromes mielodisplásicas constituem um grupo de doenças de ordem clonal hematopoética evidenciadas por estudos em todo o mundo. A estimativa de sobrevida dos pacientes e de casos que apresentam evolução leucêmica requer investigação na população brasileira, pois não se conta com nenhum dado dessa natureza. Assim, este estudo objetivou caracterizar e estimar a sobrevida e evolução leucêmica de portadores de síndromes mielodisplásicas acompanhados em um serviço de referência. Trata-se de um estudo de coorte retrospectiva realizada de janeiro de 2000 a dezembro de 2010. Para análise descritiva foi utilizado o programa Epi Info 2002, versão 3.5.2, e para os cálculos das probabilidades de sobrevida foi empregado o método de Kaplan-Meier pelo uso do programa Statistic Package for Social Sciences (SPSS), versão 10.0. Os cálculos da probabilidade de associação entre as características analisadas e o gênero foram realizados pelos testes do qui-quadrado de tendência, de Fisher, Mann Whitney, e de Log Rank. O nível de significância considerado foi de 0,05. O trabalho foi aprovado em seus aspectos ético e metodológico pelo Comitê de Ética em Pesquisa do Hospital Universitário Onofre Lopes (HUOL), sob o Protocolo n. 432/10. Dos 29 pacientes selecionados, houve predomínio de idosos, do sexo masculino, com baixa escolaridade. Apresentaram baixa probabilidade acumulada de sobrevida e índices de evolução leucêmica em torno de 27%, sem nenhum resultado satisfatório para o tratamento quimioterápico, bem como nenhuma indicação de transplante de medula óssea como possibilidade de cura. Fazem-se necessárias pesquisas com populações maiores para caracterização em todo território nacional.

How does bone marrow transplantation affect ovarian function and fertility?

This article sets out to review the literature on gonadal toxicity of bone marrow transplantation (BMT) in women, and preventive and curative actions available for girls and women facing BMT and infertility. The real incidence of ovarian damage after BMT is difficult to assess. Series reporting ovarian function and pregnancies after BMT vary greatly in terms of endpoints, number of patients included, age at and indications for BMT, conditioning regimens and duration of follow-up. The risk of premature ovarian failure (POF) is very high, however, and increases with age and in case of BMT conditioning treatment with total body irradiation. Embryo, oocyte and ovarian cortex cryopreservation are effective fertility preservation methods that should be discussed with all girls and young women requiring BMT. Despite a lack of literature on long-term follow-up of fertility after BMT in large populations, it is clear that the risk of ovarian damage and POF is very high. Fertility preservation options should therefore be discussed with all patients having to undergo BMT.

Doação voluntária de medula óssea: comparação entre não doadores e doadores cadastrados

Introdução: Há pacientes com indicação de transplante de medula óssea que não possuem doadores compatíveis na família e dependem de doadores voluntários. Objetivo: Comparar os perfis de não doadores e de doadores voluntários de medula óssea cadastrados no Redome. Métodos: Selecionaram-se 180 indivíduos, de ambos os sexos, sendo 80 não doadores (grupo I), e 100, doadores (grupo II). Resultados: Etnia, sexo, estado civil e opção religiosa não diferiram entre os grupos, porém média de idade (p=0,001) e número de filhos (p=0,02) foram foi maior no grupo I. O grupo II apresentou maior nível de escolaridade (p=0,04) e boa condição de saúde (p=0,004). Solidariedade e campanhas de divulgação foram apontadas como fatores favoráveis ao cadastramento. Conclusão: Conclui-se que escolaridade e acesso a informações são fundamentais para a tomada de decisão do indivíduo quanto a cadastrar-se como doador voluntário de medula óssea.

Perspectivas para a leucemia mielóide aguda na infância após a observação de um grupo de pacientes tratados convencionalmente

Modern treatment of acute myeloid leukemias follows well defined guidelines: precise clinical and biological characterization, adequate aggressive chemotherapy, intensive supportive care and eventual early indication of bone marrow transplantation. In this report we present the best results obtained with conventional chemotherapy delivered to a group of pediatric patients between 1986 and 1996 and discuss the strategies for contemporary and more efficient regimens. Forty-three patients with de novo acute myeloid leukemias with ages between 6 months and 14.5 years, were treated with a 4-drug induction and consolidation program: AUNO, ARA-C, VCR and DEXA, followed by 60 weeks of maintenance with sequential cycles of ARAC & ASP, CICLO & ETO, DAUNO (6-TG) & ARA-C & VCR & DEXA and 6-TG & ARA-C & VCR & DEXA. CNS prophylaxis with intrathecal ARA-C was undertaken. No child underwent bone marrow transplantation in first remission. A total of 38/43 (84%) children achieved complete remission and event-free survival at 3 years was estimated at 24 ± 7%. The importance of discriminating AML in risk groups with particular attention paid to cytogenetic criteria and new modalities of treatment are discussed. The current relevance of bone marrow transplantations is emphasized.

Benefit assessment of preventive medical check‐ups in patients suffering from chronic granulomatous disease (CGD)

Chronic granulomatous disease (CGD) patients are susceptible to recurrent opportunistic infections and to recurrent or chronic inflammations of presumably non-infectious origin. Both types of manifestations are often accompanied by granuloma formation. Both can remain unnoticed until they deteriorate considerably and can become life-threatening if not treated in time. To evaluate the effectiveness of regular follow-up visits in CGD patients. Findings of imaging (ultrasound, radiographs, computer-tomography, magnetic resonance imaging), lung function tests, histopathological and microbiological assessments of biopsies have been reviewed. A total of 32 CGD patients have been evaluated within 15 years. Of these eight patients have been checked regularly for more than 5 years. Early detection prior to specific clinical signs and consecutive treatment of six lung manifestations and one liver manifestation such as interstitial pneumonia with formation of small granulomas, formation of large granulomas, fibrosis, Aspergillus infections, and abscesses could presumably prevent considerable aggravation in seemingly healthy or mildly symptomatic patients. In contrast, patients without surveillance who presented with severe symptoms (seven manifestations) often had irreversible organ damage or even died. Regular follow-up visits can help prevent or mitigate clinical manifestations, improve life quality and expectancy and weigh indication for bone marrow transplantation in CGD patients.

Non-endocrine late complications of bone marrow transplantation in childhood: part I.

Non-endocrine late complications of bone marrow transplantation in childhood: part I.

Successful unrelated bone marrow transplantation for Shwachman–Diamond syndrome

A 5-year-old boy with Shwachman-Diamond syndrome underwent unrelated HLA-identical bone marrow transplantation for severe pancytopenia. Conditioning was with busulfan, thiotepa and cyclophosphamide plus rabbit anti-lymphocyte serum. Engraftment for neutrophils and platelets was observed on days +18 and +41, respectively. Transplant-related side-effects were mild and transient. After a follow-up of 32 months, the patient is alive and enjoys a normal life, off any immunosuppressives. Immunological and hematological reconstitution is complete while other phenotypic characteristics (pancreatic insufficiency, short stature, femur dysostosis) are stable. Although experience in this field is scarce, we speculate that bone marrow failure in Shwachman-Diamond syndrome (even if not linked to the appearance of clonal disorders or leukemic transformation) is an indication for bone marrow transplantation and may be associated with a better outcome.

Bone marrow transplantation versus periodic prophylactic blood transfusion in sickle cell patients at high risk of ischemic stroke: a decision analysis

AbstractMeasurement of cerebral blood velocity (CBV) by transcranial Doppler has been used to identify patients with sickle cell disease (SCD) who are at high risk of ischemic stroke. This study examines outcomes of bone marrow transplantation (BMT) and periodic blood transfusion (PBT) as a basis for making treatment recommendations for patients who have elevated CBV and no other indications for BMT. Decision analysis was used to compare the number of quality-adjusted life years (QALYs) experienced by a population of patients with SCD at high risk for stroke who were treated with PBT or BMT. Markov models were constructed to represent the clinical course of patients with SCD who were treated with PBT or BMT. Medical literature and expert opinion provided risks of stroke and death for different disease states, estimates of transition probabilities from one clinical state to another, and quality of life. An intention-to-treat analysis and an analysis of treatment received were both performed on hypothetical cohorts of 100 000 patients. Patients with SCD who were managed with a strategy of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the variation around these estimates was large. In the treatment received analysis, patients compliant with PBT therapy and iron chelation could expect the best outcomes (19.2 QALYs). From a policy perspective, neither BMT nor PBT can be considered the “best” treatment for children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.

Bone marrow transplantation versus periodic prophylactic blood transfusion in sickle cell patients at high risk of ischemic stroke: a decision analysis

Measurement of cerebral blood velocity (CBV) by transcranial Doppler has been used to identify patients with sickle cell disease (SCD) who are at high risk of ischemic stroke. This study examines outcomes of bone marrow transplantation (BMT) and periodic blood transfusion (PBT) as a basis for making treatment recommendations for patients who have elevated CBV and no other indications for BMT. Decision analysis was used to compare the number of quality-adjusted life years (QALYs) experienced by a population of patients with SCD at high risk for stroke who were treated with PBT or BMT. Markov models were constructed to represent the clinical course of patients with SCD who were treated with PBT or BMT. Medical literature and expert opinion provided risks of stroke and death for different disease states, estimates of transition probabilities from one clinical state to another, and quality of life. An intention-to-treat analysis and an analysis of treatment received were both performed on hypothetical cohorts of 100 000 patients. Patients with SCD who were managed with a strategy of intending to provide BMT could expect 16.0 QALYs, compared with 15.7 QALYs for a strategy of intending to provide PBT; however, the variation around these estimates was large. In the treatment received analysis, patients compliant with PBT therapy and iron chelation could expect the best outcomes (19.2 QALYs). From a policy perspective, neither BMT nor PBT can be considered the “best” treatment for children with SCD who have abnormal CBV. Abnormal CBV should not be the only criterion for selecting patients with sickle cell for BMT.

Role of surgical biopsies in the management of bone marrow transplant patients.

Bone marrow transplantation (BMT) patients frequently develop life-threatening problems that have similar clinical presentations but differing aetiologies. Despite intensive investigation by haematological, biochemical, and microbiological means, accurate diagnosis is not always possible. Histological and microbiological examination of biopsies from the affected organ may be indicated to enable an accurate diagnosis to be made in these patients. Here we assess the indications, findings, and outcomes in patients who have required surgical biopsy after BMT. We retrospectively reviewed all BMT patients who had surgical biopsies between February 1994 and January 1997. Twenty-six patients (1-46 years, median age 10 years) underwent 40 biopsies from the upper and lower GI tract, lung, or liver. Indications for BMT were: relapsed leukaemia = 18; other types of leukaemia = 3; aplastic anaemia=3; other diseases = 2. Type of BMT: matched related donor = 3, unrelated T-cell depleted donor = 23. Eleven (42%) cases had a change in management; 4 (16%) patients avoided further aggressive therapy because of poor prognosis. Unexpected diagnoses were found in 7 biopsies: 1 acute colitis, 1 duodenal ulcer, 1 liver aspergilloma, 2 transfusion siderosis, 1 radiation fibrosis of the lung, and 1 cytomegalovirus infection of the lung. Three patients were noted to have complications after their procedure. Surgical biopsies for undiagnosed problems can be of benefit in the management of very sick patients who have received bone marrow transplantations. Despite the fact that these patients are so unwell, there is a low rate of complications related to surgery and anaesthesia.

Bone marrow transplantation using unrelated donors for haematological malignancies.

Bone marrow transplantation from unrelated donors is increasingly used to treat haematological malignancies. There are almost 4 million volunteer donors now available. Therefore, it is possible to find an HLA-A, -B and -DR-identical donor for around 70% of the patients. The major obstacles to unrelated bone marrow transplantations have been rejection, severe acute graft-versus-host disease (GVHD) and prolonged immune recovery leading to frequent infections and a high transplant-related mortality. However, with improved tissue typing using DNA techniques, immunosuppression using T-cell depletion in vitro or in vivo, the frequency of acute GVHD is acceptable and the results approach those obtained with HLA-identical siblings. For patients with chronic myeloid leukaemia, the worldwide 3-year survival is around 40%. Other indications for bone marrow transplantation with unrelated marrow include acute leukaemia and myelodysplastic syndromes with high-risk features. Unrelated cord blood cells and unrelated peripheral blood progenitor cells will be increasingly used as alternative haematopoietic stem cell sources to bone marrow. Improved immunosuppression, more accurate tissue typing, growth factors and better management of infections is expected to improve outcome using unrelated haematopoietic stem cells for transplantation in the near future.

Bone marrow transplantation in children with hereditary disorders.

Hereditary disorders represent a very heterogenous group of diseases affecting the hematopoietic system. Bone marrow transplantation is the treatment of choice for immunodeficiencies, mucopolysaccharidosis, thalassemia, Fancoli's anemia, osteopetrosis, and other rare disorders. Indications for bone marrow transplantation are well known when an HLA-identical sibling is identified. Results of alternative donor transplantations are still under investigation. Recently, progress has been made in the analysis of the mechanism of the disease at the molecular level and in the identification of gene mutations. Clinical implications of these discoveries might modify the future indications for bone marrow transplantation.

Acute hypoxemic respiratory failure in children following bone marrow transplantation

To describe the pulmonary pathology and clinical outcome in children with acute hypoxemic respiratory failure after bone marrow transplantation. Review of medical records and pathologic material of patients diagnosed with acute hypoxemic respiratory failure after bone marrow transplantation. Pediatric intensive care unit (ICU) of a teaching hospital. Retrospective review of a consecutive cohort of children, with a history of bone marrow transplantation admitted to the pediatric ICU during a 7-yr study period, and who met a published definition of acute hypoxemic respiratory failure. For each admission, the pediatric ICU course and outcome were reviewed. Pathologic material that was obtained from the patients was reexamined and assigned to one of the following categories: acute or organizing diffuse alveolar damage, pulmonary hemorrhage, nonspecific interstitial pneumonitis, or infectious pneumonia. None. Forty-three patients satisfied criteria for inclusion in the study group. Indications for bone marrow transplantation were: solid tumor (30%), leukemia (44%), congenital immunodeficiency (19%), and aplastic anemia (7%). Patients were admitted to the pediatric ICU a median of 1 month (range 0 to 126) after bone marrow transplantation. Thirty-eight (88%) patients died in the pediatric ICU. Tissue histologic material was available from 21 (49%) patients. Six (29%) of 21 patients had acute diffuse alveolar damage; one (5%) had organizing diffuse alveolar damage; three (14%) had nonspecific interstitial pneumonitis; and two (10%) had pulmonary hemorrhage. Infectious pneumonia occurred in nine (43%) cases (five fungal; four viral). The acute mortality rate (88%) for children with acute hypoxemic respiratory failure after bone marrow transplantation is similar to that reported for adults with this combination of conditions. Diffuse alveolar damage, the histologic hallmark of adult respiratory distress syndrome, was present in a minority (33%) of patients. Infectious pneumonia was the most frequent cause of acute hypoxemic respiratory failure in patients who had pathologic tissue available, emphasizing the need for aggressive diagnostic studies and early institution of antifungal and antiviral therapy.

10 Bone marrow transplantation for acute lymphoblastic leukaemia

Allogeneic bone marrow transplantation (BMT) has been used in the treatment of poor risk acute lymphoblastic leukaemia (ALL) for over 20 years. Over this period results have improved and indications for treatment have become more clearly defined. Over 60% of adults and over 70% of children with poor risk ALL in first remission, and 30-40% of patients in second remissions can be expected to achieve long term leukaemia-free survival. Factors implicated in the cure of ALL by BMT are the myeloablative preparative regimen, a graft-versus-leukaemia effect, and post transplant chemotherapy. Improved results of chemotherapy have changed the perceived indications for BMT in ALL and have led to controversy over the best treatment approach. However there is good evidence to show that BMT offers a better chance of leukaemia free survival in certain very poor risk categories. These include Philadelphia chromosome positive ALL, remission induction failures, and children in second remission who relapse after adequate chemotherapy. Particular issues in the use of BMT in ALL are the prevention and management of extramedullary leukaemia, the treatment of relapse following BMT, and the prevention and monitoring of late effects. In the future the use of unrelated donors, and a continuing fall in transplant related morbidity and mortality will extend the use of BMT in poor risk ALL.

GONADAL FUNCTIONS IN 24 PATIENTS AFTER BONE MARROW TRANSPLANTATION

The long term follow-up of patients after bone marrow transplantation (BMT) allows for a more precise definition of its potential side-effects. Gonadal functions are potentially sensitive to several procedures regularly used for BMT preparations, either total body irradiation (TBI) or high dose regimen chemotherapy. We present a series of 24 patients aged at least 14 years previously treated by BMT, either before or after onset of puberty. There were 17 boys and 7 girls. Mean age at BMT was 13,2 for the boys and 11,2 tor the girls. 11 did not show any sign of pubertal development at the time of BMT. The indications for BMT were ALL in 11, ANLL in 2, lymphoma in 4, Chronic leukemia in 1, aplastic anaemia in 4 and solid tumors in 1. 13 received allogenic BMT and 11 autologous BMT. All the 7 girls, whatever the types of preparations and BMT, developed severe ovarian failure. Of the 17 boys, all 5 who have received previously testicular irradiation for ALL relapse and TBI before BMT have evidences of leydigian dysfunction (Δ). The evolution of the others 12 is summarized in the table according the status of puberty and conditioning regimens. Of the 9 given chemotherapy only, 3 were prepubere at BMT and 2 of these developed Sertolian dysfunction. In conclusion, this study confirms the constant ovarian dysfunction after BMT in girls. For the boys even in the group of patients given only chemotherapy there was evidence of secondary testicular dysfunction regardless of the respective timing ot BMT and the onset of puberty.