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Objective: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT).Study Design: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units.Results: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents.Conclusions: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children. [ABSTRACT FROM AUTHOR]

Long-term survival rates in childhood acute lymphoblastic leukemia (ALL) are currently above 85% due to huge improvements in treatment. However, 15-20% of children still experience relapses. Relapses can either occur in the bone marrow or at extramedullary sites, such as gonads or the central nervous system (CNS), formerly referred to as ALL-blast sanctuaries. The reason why ALL cells migrate to and stay in these sites is still unclear. In this review, we have attempted to assemble the evidence concerning the microenvironmental factors that could explain why ALL cells reside in such sites. We present criteria that make extramedullary leukemia niches and solid tumor metastatic niches comparable. Indeed, considering extramedullary leukemias as metastases could be a useful approach for proposing more effective treatments. In this context, we conclude with several examples of potential niche-based therapies which could be successfully added to current treatments of ALL. [ABSTRACT FROM AUTHOR]

Objective: To assess school performance in an unselected group of childhood cancer survivors and study risk factors for impairment. Study design: Rates of repeating a grade were compared for patients with cancer, their siblings, and the general population. Phone questionnaires were administered to patients about the school career of their child in remission and their siblings. Responses about cancer survivors were compared with those concerning their siblings and various registries provided by the national board of education. The primary outcome was the rate of repeating a grade. Results: A total of 148 children in remission with a mean age of 15 ± 5.3 years and a mean follow-up period since diagnosis of 6.3 ± 1.3 years were included. More patients than siblings repeated a grade (33% versus 21%; P = .02), with a mean delay since diagnosis of 2 years. Risk factors were an older age at diagnosis, attending a secondary school, low education level of parents, bone marrow transplantation, cerebral surgery, and physical sequelae. In multivariate analysis, risk for repeating was associated with low educational level of the father, attending secondary school at diagnosis, and requiring school-organized educational support on return to school. Conclusion: After cancer, repeating a grade is not an exceptional occurrence, especially for teenagers; follow-up and supportive interventions before returning to school would be beneficial. [ABSTRACT FROM AUTHOR]

Abstract: CD9 has been shown to be differentially expressed in childhood TEL/AML1-positive acute lymphoblastic leukemia (ALL). We confirmed this finding in large Affymetrix data sets and in 80 new cases at both RNA and protein levels. Moreover, we showed that mean fluorescence intensity of CD9 by flow cytometry can distinguish TEL/AML1-positive ALL from other BCP-ALL. Using ROC analysis, the most efficient model for predicting TEL/AML1-positive ALL combined CD9 (mean fluorescence intensity ≤20) and CD10 values (positive cells >40%). Finally, we propose a faster procedure for optimizing the diagnosis of childhood BCP-ALL subgroups. [Copyright &y& Elsevier]

The failure to chemotherapy is a multi factorial phenomenon and lung resistance protein (LRP) overexpression has already been discussed as implicated in drug resistance. But its role is still discussed. In 1996, we studied the expression of LRP and P170 (MDR) in a series of leukemias, at the time of diagnosis, by immunocytochemical (ICC) method. The observation of a strong and unusual expression of LRP in acute myeloid leukemia (AML) with monocytic component led us to test (for P170 and LRP) a new series of 47 AML with different FAB subtypes. The expression of LRP was scored from 1 to 5 in blast cells and monocytes separately. We demonstrate that LRP is not correlated with clinical outcome but is statistically related to monoblastic leukemias. Code 5 reaction was found in 10/13 M5 versus the other FAB subtypes (P<10−3). The strongest LRP overexpression was also found in chronic myelomonocytic leukemia (four cases), reactive monocytosis (three cases) and in a dendritic cell line.In conclusion, we report that LRP is rather a marker of monocytic lineage than a prognostic index for MDR and we suggest that detection of LRP by ICC could be an argument for the diagnosis of monoblastic and monocytic leukemias. [Copyright &y& Elsevier]

Objective: To evaluate the association between medical and social environmental factors and the risk of repeating a grade in childhood leukemia survivors.Study Design: A cross-sectional study of childhood leukemia survivors, recruited through the LEA cohort (Leucémie de l'Enfant et de l'Adolescent [French Childhood Cancer Survivor Study for Leukemia]) in 2014. An adjusted logistic regression model was used to identify variables linked to repeating a grade after the diagnosis among the survivors, and the rates of repeating a grade were compared between the survivors and their siblings using a multilevel logistic regression model.Results: The mean age at inclusion of the 855 participants was 16.2 ± 7.0 years, and the mean duration of follow-up from diagnosis to evaluation was 10.2 ± 6.2 years. After disease onset, 244 patients (28.5%) repeated a grade, with a median interval of 4 years (IQR, 2-8 years). Independent factors associated with repeating a grade were male sex (OR, 1.78; 95% CI, 1.21-2.60), adolescence (OR, 2.70; 95% CI, 1.63-4.48), educational support during the treatment period (OR, 3.79; 95% CI, 2.45-5.88), low parental education level (OR, 2.493; 95% CI, 1.657-3.750), and household financial difficulties (OR, 2.62; 95% CI, 1.607-4.28). Compared with siblings, survivors were at greater risk of repeating a grade (OR, 1.87; 95% CI, 1.48-2.35).Conclusions: The most vulnerable patients seemed to be adolescents and those with parents of low socioeconomic status. Improving the schooling career of leukemia survivors will require that the medical community more carefully consider the social status of patients. [ABSTRACT FROM AUTHOR]

Objective: To gain insight into how primary immunodeficiencies (PIDs) affect children's health status and quality of life.Study Design: The French Reference Center for PIDs conducted a prospective multicenter cohort that enrolled participants who met all criteria: patients included in the French Reference Center for PIDs registry, children younger than18 years, and living in France. Participants were asked to complete both a health questionnaire and a health-related quality of life (HR-QoL) questionnaire. A severity score was assigned to each health condition: grade 1 (mild) to grade 4 (life-threatening). HR-QoL in children was compared with age- and sex-matched French norms.Results: Among 1047 eligible children, 656 were included in the study, and 117 had undergone hematopoietic stem cell transplantation; 40% experienced at least one grade 4 condition, and 83% experienced at least one grade 3 or 4 condition. Compared with the French norms, children with PID scored significantly lower for most HR-QoL domains. Low HR-QoL scores were associated strongly with burden of poor conditions.Conclusions: Our results quantify the magnitude of conditions in children with PID and demonstrate that the deleterious health effects borne by patients already are evident in childhood. These results emphasize the need to closely monitor this vulnerable population and establish multidisciplinary healthcare teams from childhood.Trial Registration: ClinicalTrials.gov: NCT02868333 and EudraCT 2012-A0033-35. [ABSTRACT FROM AUTHOR]

Background Most children with primary immunodeficiencies (PIDs) now reach adulthood. However, few studies have evaluated their health status and health-related quality of life (HRQoL). Objective To investigate long-term morbidity, the French Reference Center for PIDs initiated a prospective multicenter cohort: the French Childhood Immune Deficiency Long-term Cohort. The data collected were used to assess the physical health condition of patients who reached adulthood and the effect on their quality of life. Methods Patients were asked to complete health status questionnaires. A severity score (grade 1 [mild] to grade 4 [life-threatening]) was assigned to each health condition. The HRQoL of patients was compared with age- and sex-matched French normal values by using the 36-item Short-Form Survey (SF-36) HRQoL questionnaire. Results Among 329 participants, the mean age at evaluation was 27.6 years, with a 21-year mean follow-up after diagnosis; 43% reported at least 1 grade 4 health condition, and 86% reported at least 1 grade 3 (severe) or 4 health condition. Twenty-five (7.6%) patients had been treated for cancer. Compared with the French normal values, adults with PIDs scored significantly lower for all HRQoL domains. HRQoL was strongly associated with the burden of health conditions. The association with grade 4 or grade 3-4 health conditions was highly significant for all physical and mental domains. Conclusion Adults with PIDs diagnosed during childhood experienced a heavy burden of health conditions, which affected their HRQoL. Our results emphasize the need to closely monitor this vulnerable population. [ABSTRACT FROM AUTHOR]

Background We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections. Objective We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency. Methods We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment. Results We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8 + T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities. Conclusion Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency. [ABSTRACT FROM AUTHOR]

To study the impact of hematopoietic stem cell transplantation (HSCT) on the uterine volume of childhood acute leukemia (AL) survivor depending on age at HSCT and the type of myeloablative conditioning regimen. Thirteen French University Teaching Hospitals. Prospective cohort study. Eighty-eight women who underwent HSCT during childhood or adolescence for AL compared to a control group. A multicentric prospective national study compared the uterine volume in a cohort of childhood AL survivor adult women treated with HSCT, matched 1:1 to control women. Pelvic magnetic resonance imaging scans included diffusion-weighted imaging sequences. Scans were centralized for a double-blinded reading by 2 radiologists. Uterine volume, uterine body-to-cervix ratio, and apparent diffusion coefficient. The mean age at HSCT was 9.1 ± 0.3 years with a mean follow-up duration of 16.4 ± 0.5 years. The cohort of 88 HSCT survivor women was composed of 2 subgroups depending on the myeloablative conditioning regimen received: an alkylating agent–based regimen group (n = 34) and a total body irradiation (TBI)–based regimen group (n = 54). Among the 88 women, 77 were considered as having a "correct hormonal balance" with estrogens supplied by hormone replacement therapy (HRT) for premature ovarian insufficiency (POI) or because of a residual ovarian function. In the control group (n = 88), the mean uterine volume was 79.7 ± 3.3 mL. The uterine volume significantly decreased in all HSCT survivor women. After the alkylating agent–based regimen, the uterine volume was 45.3 ± 5.6 mL, corresponding to a significant volume reduction of 43.1% (28.8–57.4%) compared with that of the control group. After TBI, the uterine volume was 19.6 ± 1.9 mL, corresponding to a significant volume reduction of 75.3% (70.5%–80.2%) compared with that of the control group. After the alkylating agent–based regimen, the uterine volume dramatically decreased in women with POI without HRT compared with that in those with a correct hormonal balance (15.2 ± 2.6 vs. 49.3 ± 6 mL). In contrast, after TBI, the uterine volume was similar in all women, with no positive effect of hormonal impregnation on the uterine volume (16.3 ± 2.6 vs. 20.1 ± 2.2 mL, respectively). The uterine volume was diminished after HSCT, regardless of the conditioning regimen. The physiopathology needs to be further investigated: specific impact of a high dose of an alkylating agent; impact of hormone deprivation around puberty; poor compliance to HRT; or different myometrial impact of HRT compared with endogenous ovarian estrogens? ClinicalTrials.gov/NCT 03583294 (enrollment of the first subject, November 11, 2017; enrollment of the last subject, June 25, 2021). [ABSTRACT FROM AUTHOR]

Abstract: We describe here a late extramedullary ovarian relapse in an 18-year-old female who was diagnosed with hypotetraploid cell acute lymphoblastic leukaemia (cALL) at the age of 6. At both occurrences of the disease cells were analyzed by morphology, immunophenotyping, cytogenetics and molecular methods. TEL/AML1 was detected by RT-PCR and FISH analysis in both events. We demonstrated, using detection of IGH/TCR rearrangements and TEL/AML1 breakpoints sequencing that the cells were clonally related. Moreover, interphasic FISH using TEL and AML1 probes showed the loss of a second TEL at the time of relapse. This observation confirms that TEL/AML1 alone is not sufficient to trigger ALL and that TEL deletion is a secondary event in leukemogenesis. To our knowledge, it is the first complete description of extramedullary ALL relapse combining all methodologies. [Copyright &y& Elsevier]

Highlights • Umbilical cord blood transplantation (UCBT) offers high survival rates in children and young adults with acute leukemia. • Even with positive pretransplantation minimal residual disease (MRD), UCBT leads to high cure rate. • Double UCBT may have a better graft-versus-leukemia effect in patients with MRD. ABSTRACT We previously reported in a French prospective randomized study that transplantation of 2 unrelated cord blood (UCB) units instead of 1 unit does not decrease the risk of transplantation failure but may enhance alloreactivity. Here we evaluated the influence of pretransplantation minimal residual disease (MRD) on leukemia relapse and survival after single- versus double-UCB transplantation (UCBT). Among 137 children and young adults who underwent UCBT in this randomized study, 115 had available data on MRD assessment done immediately before initiation of the pretransplantation conditioning regimen. MRD was considered positive at a level of ≥10−4, which was the case of 43 out of 115 patients. Overall, the mean 3-year survival probability was 69.1 ± 4.4%, and it was not significantly influenced by the MRD level: 70.7 ± 5.4% in MRD-negative (<10−4) patients (n = 72), 71.1 ± 9.4% in MRD-positive patients with 10−4 ≤ MRD <10−3 (n = 26) and 58.8 ± 11.9% in MRD-positive patients with ≥10−3 (n = 17). In the MRD-positive group, the mean risk of relapse was significantly lower in the double-UCBT arm compared with the single-UCBT arm (10.5 ± 7.2% versus 41.7 ± 10.4%; P =.025) leading to a higher mean 3-year survival rate (82.6 ± 9.3% versus 53.6 ± 10.3%; P =.031). This difference was observed only in patients who had not received antithymocyte globulin during their conditioning regimen. In the MRD-negative group, there was no differencebetween the single- and the double-UCBT arms. We conclude that even in cases of positive pretransplantation MRD, UCBT in children and young adults with acute leukemia yields a high cure rate, and that a double-unit strategy may enhance the graft-versus-leukemia effect and survival in these patients. [ABSTRACT FROM AUTHOR]

We compared the long-term impact of donor type (sibling donor [SD] versus matched unrelated donor [MUD] or umbilical cord blood [UCB]) on late side effects and quality of life (QoL) in childhood acute leukemia survivors treated with hematopoietic stem cell transplantation. We included 314 patients who underwent transplantation from 1997 to 2012 and were enrolled in the multicenter French Leucémie de l'Enfant et de L'Adolescent (“Leukemia in Children and Adolescents”) cohort. More than one-third of the patients were adults at last visit; mean follow-up duration was 6.2 years. At least 1 late effect was observed in 284 of 314 patients (90.4%). The average number of adverse late effects was 2.1 ± .1, 2.4 ± .2, and 2.4 ± .2 after SD, MUD, and UCB transplantation, respectively. In a multivariate analysis, considering the SD group as the reference, we did not detect an impact of donor type for most sequelae, with the exception of increased risk of major growth failure after MUD transplantation (odds ratio [OR], 2.42) and elevated risk of osteonecrosis after UCB transplantation (OR, 4.15). The adults and children's parents reported comparable QoL among the 3 groups. Adult patient QoL scores were lower than age- and sex-matched French reference scores for almost all dimensions. We conclude that although these patients are heavily burdened by long-term complications, donor type had a very limited impact on their long-term health status and QoL. [ABSTRACT FROM AUTHOR]

Relapses of acute lymphoblastic leukemia (ALL) early after hematopoietic stem cell transplantations in children are uncommon but associated with a very poor prognosis. Whereas there are no current recommendations for the management of these relapses, the children's quality of life is an important issue. We studied the outcomes, including 1-year overall survival, complete remission, and quality of life, of 19 children with ALL who relapsed within the first year after their transplantation treated in the 5 participating centers between 2000 and 2011 Patients were distributed as follows: supportive care only (group A), outpatient treatment (mainly steroid and vincristine, group B), or intensive inpatient treatment (group C). There were no significant differences in 1-year overall survival (31.5% for the entire cohort) or remission rate for time between transplantation and relapse (< 6 months or 6 to 12 months), transplantation or disease characteristics, or treatment group. However, time spent in hospital (for treatment and complications) significantly differed between treatment groups B and C (20.8% ± 13.0 versus 59.1% ± 32.9, respectively; P < .05). No differences in organ toxicities, school attendance, or Lansky scores were found between treatment groups. Our sample size–limited data indicate, in a prepersonalized medicine era, that children treated with steroid and vincristine have the same prognosis as those treated with intensive therapy, but they may benefit from improved quality of life. Nevertheless, new therapeutic strategies are required and future prospective trials would help to establish recommendations. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemias (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Current survival rates roughly reach 90% at 10 years from diagnosis. However, 15–20% of children still relapse with a significant risk of death. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into sanctuary sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCL12). Here, we identified common factors shared by the bone marrow and extramedullary niches which could upregulate CD9 expression and function. We found that low oxygen levels enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1α (HIF1α), the master transcription factor involved in hypoxia response, binds directly CD9 promoter and induce CD9 transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1α signaling pathway promotes ALL cells engraftment in a CD9-dependent manner. The present work increments our understanding of CD9 implication in ALL pathogenesis. • Tetraspanin CD9 expression is regulated by low O 2. • The Hypoxia Inducible Factor 1α (HIF1α) signaling pathway is directly involved. • CD9-mediated migration and dissemination depends on the HIF1α signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. Methods Retrospective data from 81 children less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). Results A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall ( p < 10 −4 ) irrespective of gender and pubertal age. The height SDS was significantly ( p < 10 −4 ) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. Conclusion Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents. [ABSTRACT FROM AUTHOR]

Summary: Background: Trials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug''s role when given with multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin–Frankfurt–Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL. Methods: Patients aged 1–18 years recruited to national trials of front-line treatment for ALL were eligible if they had t(9;22)(q34;q11). Patients with abnormal renal or hepatic function, or an active systemic infection, were ineligible. Patients were enrolled by ten study groups between 2004 and 2009, and were classified as good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned by a web-based system with permuted blocks (size four) to receive post-induction imatinib with chemotherapy or chemotherapy only in a 1:1 ratio, while all poor-risk patients received post-induction imatinib with chemotherapy. Patients were stratified by study group. The chemotherapy regimen was modelled on a Berlin–Frankfurt–Munster high-risk backbone; all received four post-induction blocks of chemotherapy after which they became eligible for stem-cell transplantation. The primary endpoints were disease-free survival at 4 years in the good-risk group and event-free survival at 4 years in the poor-risk group, analysed by intention to treat and a secondary analysis of patients as treated. The trial is registered with EudraCT (2004-001647-30) and ClinicalTrials.gov, number NCT00287105. Findings: Between Jan 1, 2004, and Dec 31, 2009, we screened 229 patients and enrolled 178: 108 were good risk and 70 poor risk. 46 good-risk patients were assigned to receive imatinib and 44 to receive no imatinib. Median follow-up was 3·1 years (IQR 2·0–4·6). 4-year disease-free survival was 72·9% (95% CI 56·1–84·1) in the good-risk, imatinib group versus 61·7% (45·0–74·7) in the good-risk, no imatinib group (p=0·24). The hazard ratio (HR) for failure, adjusted for minimal residual disease, was 0·63 (0·28–1·41; p=0·26). The as-treated analysis showed 4-year disease-free survival was 75·2% (61·0–84·9) for good-risk patients receiving imatinib and 55·9% (36·1–71·7) for those who did not receive imatinib (p=0·06). 4-year event-free survival for poor-risk patients was 53·5% (40·4–65·0). Serious adverse events were much the same in the good-risk groups, with infections caused by myelosuppression the most common. 16 patients in the good-risk imatinib group versus ten in the good-risk, no imatinib group (p=0·64), and 24 in the poor-risk group, had a serious adverse event. Interpretation: Our results suggests that imatinib in conjunction with intensive chemotherapy is well tolerated and might be beneficial for treatment of children with Philadelphia-chromosome-positive ALL. Funding: Projet Hospitalier de Recherche Clinique-Cancer (France), Fondazione Tettamanti-De Marchi and Associazione Italiana per la Ricerca sul Cancro (Italy), Novartis Germany, Cancer Research UK, Leukaemia Lymphoma Research, and Central Manchester University Hospitals Foundation Trust. [Copyright &y& Elsevier]

Information is scarce on outcomes after unrelated cord blood transplantation (UCBT) for patients with severe aplastic anemia (SAA). We retrospectively analyzed 71 patients (median age, 13 years; 28 adults) with SAA (9 with paroxysmal nocturnal hemoglobinuria [PNH]) who received a single-unit (n = 57; 79%) or double-unit UCBT (n = 14; 19%) in 32 centers between 1996 and 2009. A reduced-intensity conditioning regimen was provided in 68% of the patients. The cumulative incidence (CI) of neutrophil recovery was 51% ± 6% at day 60, with significantly better engraftment seen in recipients of higher prefreezing total nucleated cell (TNC) dose (>3.9 107/kg; hazard ratio [HR], 1.5; P = .05). The CI of platelet engraftment at day 180 posttransplantation was 37% ± 7%, that of grade II-IV acute GVHD was 20% ± 5%, and that of chronic GVHD at 3 years was 18% ± 5%. At a median follow-up of 35 months (range, 3-83 months), the estimated probability of 3-year overall survival (OS) was 38% ± 6%. Significantly improved OS was seen in recipients of >3.9 107 TNCs/kg prefreezing (45%, compared with 18% for recipients of ≤3.9 107 TNC/kg; HR, 0.4; P = .007). These results highlight the fundamental role of cell dose for both engraftment and OS in patients with SAA undergoing UCBT. [ABSTRACT FROM AUTHOR]

It has been reported in the literature that a leukemic cell may be (or become) resistant to anti-cancer treatment because many mechanisms, such as efflux membrane pump (multi-drug resistance, MDR-P170), intracellular transport (LRP, MRP), or different detoxification systems (glutathione transferases, methallothioneines) may be implicated. Topoisomerase II alpha (TopoII) are also reported as responsible for resistance since their main action is to repair DNA breakage. Polyamines are described as having a protective DNA action by stabilizing the double stranded DNA helix. For these reasons we investigated 65 children with acute lymphoblastic leukemia using an immunocytochemical method to elucidate the potential role of Topoisomerase and polyamines in drug resistance. Most children (60/65) were treated with the French (acute lymphoblastic leukemia, ALL) protocol (FRALLE-93) in which B and C arms include (at least) VP16. Children with cytoplasmic TopoII positivity (18 cases) were more resistant since their overall survival was 34 months compared to more than 110 months for negative cases (P=0.0003). Polyamines may be associated with drug resistance since the overall survivals were 51 months and 92 months for positive and negative patients, respectively, but the P-value is only 0.13. We conclude that Topoisomerase and polyamines must be tested at diagnosis as new possible markers for chemo-resistance. Larger series are needed to confirm these preliminary results and to verify if the use of anti epipodophillotoxin agents (as it is the case for FRALLE B or C) should be excluded for positive cases. [Copyright &y& Elsevier]