La clofarabine dans les leucémies aigües de l'enfant réfractaires ou en rechute (expérience niçoise)

Le pronostic des leucémies aigües (LA) réfractaires ou en rechute reste extrêmement péjoratif chez l enfant. La Clofarabine, nouvel analogue nucléosidique, est indiquée dans les LA de l enfant réfractaires ou en rechute après au moins deux lignes de traitement. L objectif de ce travail est de rapporter l'expérience de l'utilisation de la Clofarabine dans les LA de l enfant au sein du service d onco-hématologie pédiatrique de Nice tant en termes de tolérance que d efficacité. Nous avons réalisé une étude rétrospective sur une période de 4 ans des dossiers de tous les patients pris en charge pour une LA et traités par Clofarabine. Les données recueillies portaient sur le type de leucémie, les facteurs pronostiques associés, les traitements reçus avant la Clofarabine, la tolérance et l'efficacité ainsi que le devenir de ces patients. L efficacité de la Clofarabine était évaluée en fonction du taux de réponse global observé immédiatement après avoir bénéficié du traitement. Sur 7 patients inclus dans l étude : 5 patients ont reçu l association clofarabine/cyclophosphamide/étoposide sur une durée de 5 jours et 2 patients ont été traités par une bithérapie clofarabine/aracytine. Tous ont présenté au moins un effet secondaire mais avec une tolérance acceptable. Le taux de réponse global était de 86%. 6 patients ont pu bénéficier d une allogreffe de moelle. 3 patients (43%) sont actuellement en rémission. Malgré une petite cohorte, notre étude confirme l efficacité de la Clofarabine dans les LA réfractaires ou en rechute. La tolérance est acceptable et 86% des patients ont pu être greffés ce qui est l objectif en cas de maladie réfractaire. Ce traitement permet d obtenir une rémission chez des patients en échec des précédentes chimiothérapies. Les perspectives actuelles concernent l utilisation de la Clofarabine de manière plus précoce notamment dès la première rechute dans les leucémies du groupe haut risque.NICE-BU Médecine Odontologie (060882102) / SudocSudocFranceF

Adolescence and Socioeconomic Factors: Key Factors in the Long-Term Impact of Leukemia on Scholastic Performance—A LEA Study

International audienceOBJECTIVE: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

Late cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the LEA program

International audienceLate cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the L.E.A. program Prognosis of pediatric acute myeloid leukemia (AML) has improved significantly over the past two decades with survival rates now approaching 70%. 1 Therapy consists of a limited number of intensive chemotherapy courses mainly based on cytarabine and anthracycline. 2,3 Many pediatric late anthracycline cardiotoxicity studies have concerned heterogeneous diagnostic groups. Moreover, single childhood cancer studies were mainly conducted in acute lym-phoblastic leukemia, whereas the highest doses of anthra-cycline are given in children with AML. 4-6 We report here a prospective multi-centric study of late cardiotoxicity in 185 patients surviving childhood AML. All were treated after 1989 in French clinical trials using intensive chemotherapy alone or chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). L.E.A. (Leucémie Enfant & Adolescent) is a French prospective long-term follow-up program involving all childhood acute leukemia survivors treated in the participating centers since 1980. Details of the programm are provided elsewhere. 7 As of 31 December 2011, 282 childhood AML survivors fulfilled the L.E.A. inclusion criteria and 218 (77.3%) of them agreed to participate. Among these 218, 185 were treated according to one of the 6 multicenter trial protocols ongoing in France after January 1989. All 185 had serial echocardiographic examination as part of their L.E.A. program, and all were included in the present study. All provided written informed consent. Cardiotoxicity was defined by either clinical symptoms of congestive heart failure or by an abnormal echocardiographic left ventricular function. Left ventricular function was considered abnormal when the shortening fraction (SF) was less than 28% or when the left ventricular ejection fraction (LVEF) was less than 55% on 2D echocardiography. 8-10 Cardiotoxicity was classified as late when it started or persisted beyond one year after the completion of first-line treatment. 9 Cumulative anthracycline doses used in each trial are described in the Online Supplementary Table S1, as well as the doxorubicin-equivalent doses using conversion factors of 0.83, 4.0 and 5.0 for daunorubicin, mitoxantrone and idarubicin, respectively. 10,11 Assessment of health status, long-term late effects on health-related quality of life (QoL), and statistical analysis are described in the Online Supplementary Appendix. Characteristics of the study cohort are summarized in Table 1. Median age at the time of AML diagnosis and median follow-up duration to last cardiac evaluation were 6.53 and 9.5 years, respectively. Thirty-seven patients had a history of relapse. Median cumulative anthracycline dose was 372 mg/m² (Online Supplementary Figure S1). Ninety-nine patients were treated by chemotherapy alone, whereas the other 86 patients also received HSCT (57 in first remission, 25 in second remission, and 4 in more advanced disease). Thirty children received total body irradiation (TBI), but only 10 among the 57 transplanted in first remission did so. Median number of echographic evaluations was 3 per patient. Subclinical cardiotoxicity (SCC) was observed in 23 of 185 patients (12.4%) at least once during their follow-up program. Median time from AML diagnosis to SCC detection was 4.40 years. In these 23 patients, the median value of the worst SF was 27% and the median value of the worst LVEF was 52. Only 3 of 23 patients had a worse SF value of less than 25% (2 had 20%; 1 had 24%). Six of 23 received anti-congestive therapy and none had cardiac transplantation. Five of those receiving anti-congestive therapy were still being treated at time of last evaluation, and 4 had more than 28% SF and more than 55% LVEF. Seventeen patients never received treatment: 11 had spontaneous improvement with more than 28% SF and more than 55% LVEF at last evaluation. Finally, at last cardiac evaluation, only 8 patients had an abnormal left ventricular function. Cumulative incidence (CI) of cardiotoxicity, estimated by the Kaplan-Meier method was 16% and 27% at 10 and 15 years, respectively (Figure 1A). CI of anti-conges-tive treatment at the same follow-up times was 5% and 7%. The risk of developing cardiotoxicity depended on a previous history of relapse and on the cumulative anthracy-cline dose. At ten years from diagnosis, CI was 35% versus 11% in patients with or without history of relapse (P=0.02) (Figure 1B). Among 148 patients without any history of relapse, 10-year CI of cardiotoxicity was 14% in 97 patients treated with chemotherapy alone versus 8% in 51 patients who underwent HSCT in first remission (NS, Figure 1C). In transplanted children, the risk was not modified by either a grade 2-4 acute or an extensive chronic graft-versus-host disease. The CI of anti-congestive treatment in these 148 patients who never experienced relapse was 3% at ten an

Late thyroid complications in survivors of childhood acute leukemia. An LEA study

International audienceThyroid complications are known side effects of irradiation. However, the risk of such complications in childhood acute leukemia survivors who received either central nervous system irradiation or hematopoietic stem cell transplantation is less described. We prospectively evaluated the incidence and risk factors for thyroid dysfunction and tumors in survivors of childhood acute myeloid or lymphoid leukemia. A total of 588 patients were evaluated for thyroid function, and 502 individuals were assessed for thyroid tumors (median follow-up duration: 12.6 and 12.5 years, respectively). The cumulative incidence of hypothyroidism was 17.3% (95% CI: 14.1-21.1) and 24.6% (95% CI: 20.4-29.6) at 10 and 20 years from leukemia diagnosis, respectively. Patients who received total body irradiation (with or without prior central nervous system irradiation) were at higher risk of hypothyroidism (adjusted HR: 2.87; P=0.04 and 2.79, P=0.01, respectively) as compared with transplanted patients who never received any irradiation. Patients transplanted without total body irradiation who received central nervous system irradiation were also at higher risk (adjusted HR: 3.39; P=0.02). Patients irradiated or transplanted at older than 10 years of age had a lower risk (adjusted HR: 0.61; P=0.02). Thyroid malignancy was found in 26 patients (5.2%). Among them, two patients had never received any type of irradiation: alkylating agents could also promote thyroid cancer. The cumulative incidence of thyroid malignancy was 9.6% (95% CI: 6.0-15.0) at 20 years. Women were at higher risk than men (adjusted HR: 4.74; P=0.002). In conclusion, thyroid complications are frequent among patients who undergo transplantation after total body irradiation and those who received prior central nervous system irradiation. Close monitoring is thus warranted for these patients. Clinicaltrials.gov identifier: NCT 01756599

Prolonged versus standard native E-coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.status: publishe

Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25-year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28-1·79]; test of non-inferiority: P = 0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57-1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53-1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.status: publishe

Prolonged versus standard native E-coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children’s Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Ovarian Function and Spontaneous Pregnancy After Hematopoietic Stem Cell Transplantation for Leukemia Before Puberty: An L.E.A. Cohort Study

Ovarian function impairment and infertility are among the most frequent late effects after hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate ovarian function, occurrence of premature ovarian insufficiency (POI), and spontaneous pregnancy in a large cohort of adult survivor women who had undergone HSCT for leukemia before puberty. We conducted a retrospective observational study in women from the national cohort L.E.A., the long-term French follow-up program after childhood leukemia. The median follow-up duration was 18 years (14.2-23.3) after HSCT. Among 178 women, 106 (60%) needed pubertal induction with hormone substitution treatment, whereas 72 (40%) had spontaneous menarche. After spontaneous menarche, 33 (46%) developed POI, mostly within 5 years of HSCT. Older age at time of HSCT and cryopreservation of ovarian tissue appeared as significant risk factors for POI. More than 65% of patients who underwent HSCT before the age of 4.8 years had spontaneous menarche, and almost 50% didn't have POI at last evaluation, whereas more than 85% with HSCT after the age of 10.9 years didn't have spontaneous menarche and needed induction of puberty with hormone replacement therapy. Twenty-two women (12%) had at least one spontaneous pregnancy, with 17 live-births, 14 miscarriages, 4 legal abortions, and 2 therapeutic abortions. These results add supplementary data to better counsel patients and their families on the chances of ovarian residual function and pregnancy after HSCT, as well as on the potential interest of fertility preservation

Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study.

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20 years (range 4-32 years). The 25-year disease-free survival rate (+/-SE) was 67.4 +/- 4.9% without CRT and 70.2 +/- 5.0% with CRT. The 25-year incidence of isolated (6.5 +/- 2.6% vs. 4.8 +/- 2.3%) and any CNS relapse {8.7 +/- 2.9% vs. 11.9 +/- 3.5%; hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.28-1.79]; test of non-inferiority: P = 0.01} was not increased without CRT. The 25-year SN incidence in CR1 was 7.9 +/- 4.6% vs. 11.0 +/- 4.2%. The 25-year event-free and overall survival rates were quite similar in both arms [59.5 +/- 6.3% vs. 60.5 +/- 5.9%, HR 0.94 (95% CI 0.57-1.52), and 78.1 +/- 4.3% vs. 78.5 +/- 4.5%, HR 1.00 (95% CI 0.53-1.88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL