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)
standard (short-asparaginase) native
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
asparaginase were switched to equivalent doses of
or pegylated
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;
=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89;
=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;
=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%
14.4%) and late intensification (22.6%
15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30%
21%). Prolonged native
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.
Thyroid 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.
We evaluate the prevalence and risk factors of the metabolic syndrome (MS) in young adults surviving childhood leukemia. During the years 2007 to 2008, assessment of MS was proposed to all adults ...included in the Leucémie de l'Enfant et de l'Adolescent program, a French prospective multicentric cohort of leukemia survivors. Among 220 eligible patients, 184 (83.6%) had complete evaluation. Median age at evaluation and follow-up duration were 21.2 and 15.4 years. Overall prevalence of MS was 9.2% (95% confidence interval, 5.5-14.4). There was no association of MS with sex, age at diagnosis, leukemia subtype, steroid therapy, and central nervous system irradiation. Patients were stratified according to 4 therapeutic modalities: chemotherapy alone (n = 97), chemotherapy and central nervous system irradiation (n = 27), hematopoietic stem cell transplantation (HSCT) without (n = 17) or with (n = 43) total body irradiation (TBI). MS occurred in 5.2%, 11.1%, 5.9%, and 18.6% of them, respectively. The higher risk observed in the HSCT-TBI group was significant in univariate and in multivariate analysis (odds ratio OR = 3.9, P = .03). HSCT with TBI was associated with a higher rate of hypertriglyceridemia (OR = 4.5, P = .004), low level of high-density lipoprotein cholesterol (OR = 2.5, P = .02), and elevated fasting glucose (OR = 6.1, P = .04) So, TBI is a major risk factor for MS. Further studies are warranted to explain this feature.
Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric ...regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.
•Biallelic EFL1 mutations cause Shwachman-Diamond syndrome.•EFL1 deficiency impairs eIF6 eviction from nascent 60S ribosomal subunits, reducing subunit joining and attenuating protein synthesis.
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Beta thalassemias are autosomal recessive hemoglobin disorders related to a defect in the beta-globin chain production. Most of the major forms of beta-thalassemia are transfusion dependent leading ...to iron overload. Today, three iron chelators are available in France. We report the case of a patient suffering from β+ major transfusion-dependent thalassemia who presented with severe skin reactions to deferoxamine and deferasirox as well as with agranulocytosis after deferiprone administration. The patient benefited from successful tolerance induction to deferasirox. With the increasing number of children suffering from iron overload, we believe that our protocol can be useful to pediatric hematology teams confronted with multiple iron chelator reactions.
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).
El volumen uterino se ve drásticamente reducido después de un transplante de células madre hematopoyéticas durante la infancia independientemente del régimen de acondicionamiento previo.
Estudiar el impacto del transplante de células madre hematopoyéticas (HSCT) sobre el volumen uterino en las supervivientes de leucemia aguda infantil (AL) según la edad en que se realizó el HSCT y el tipo de régimen de acondicionamiento mieloablativo.
Trece hospitales universitarios franceses.
Estudio prospectivo de cohortes.
Ochenta y ocho mujeres sometidas a HSCT durante su infancia o adolescencia por AL comparadas con un grupo control.
Se comparó el volumen uterino en una cohorte de mujeres adultas supervivientes de AL infantil tratada mediante HSCT en un estudio nacional prospectivo multicéntrico, emparejadas 1:1 con mujeres control. Las imágenes de las resonancias magnéticas pélvicas incluyeron secuencias de imágenes ponderadas por difusión. Las pruebas se centralizaron para una lectura doble-ciego realizada por 2 radiólogos.
Volumen uterino, relación cuerpo-cérvix uterino y coeficiente de difusión aparente.
La edad media en la realización del HSCT fue de 9.1+/- 0.3 años, con una media de duración del seguimiento de 16.4 +/- 0.5 años. La cohorte de 88 mujeres supervivientes de HSCT estaba compuesta por 2 subgrupos dependiendo del régimen de acondicionamiento mieloablativo recibido: un grupo con régimen basado en agentes alquilantes (n=34) y otro con régimen basado en irradiación corporal total (TBI) (n=54). Entre las 88 mujeres, se consideró que 77 tenían un “balance hormonal correcto” con aporte de estrógenos mediante tratamiento hormonal sustitutivo (HRT) por insuficiencia ovárica prematura (POI) o por una función ovárica residual. En el grupo control (n=88), el volumen uterino medio fue de 79.7 +/- 3.3 mL. El volumen uterino estaba significativamente reducido en todas las mujeres supervivientes de HSCT. Tras el régimen basado en agentes alquilantes, el volumen uterino era de 45.3 +/- 5.6 mL, correspondiente a una reducción significativa del volumen del 43.1% (28.8-57.4%) comparada con las del grupo control. Después de TBI, el volumen uterino fue de 19.6 +/- 1.9 mL, correspondiente a una reducción significativa del volumen del 75.3% (70.5%-80.2%) comparadas con las del grupo control. Tras el régimen basado en agentes alquilantes, el volumen uterino disminuyó drásticamente en mujeres con POI sin HRT comparadas con aquellas que tenían un balance hormonal correcto (15.2 +/- 2.6 vs. 49.3 +/- 6 mL). Por el contrario, después de TBI, el volumen uterino fue similar en todas las mujeres, sin efecto positivo de la impregnación hormonal sobre el volumen uterino (16.3 +/- 2.6 vs 20.1 +/-2.2 mL respectivamente).
Después de HSCT se produjo una reducción del volumen uterino independientemente del régimen de acondicionamiento. Son necesarios más estudios para conocer la fisiopatología: impacto específico de altas dosis de agentes alquilantes, impacto de la deprivación hormonal en la pubertad, bajo cumplimiento del HRT o diferente impacto miometrial de la HRT comparada con los estrógenos ováricos endógenos?
Útero, transplante de células madre hematopoyéticas, MRI, quimioterapia, irradiación corporal total.
Background
To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings ...and the general population.
Methods
A cross‐sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long‐term follow‐up program, was conducted, and education‐related data were obtained via self‐report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation.
Results
A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio OR 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long‐term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population.
Conclusion
Although the results are reassuring, socioeconomic and cancer‐related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long‐term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system.
Background
Childhood cancer confront the whole family with a traumatic event. Because brothers and sisters may encounter emotional problems that can remain for a long time and that only few studies ...have assessed their long‐term outcome, our present objectives were to describe the long‐term quality of life (QoL) of childhood leukemia survivors' siblings and to explore its determinant.
Methods
Brothers and sisters (from 8‐year‐old) of survivors included in the French LEA Cohort completed a QoL questionnaire (according to their age). Scores were compared with those reported by age‐ and gender‐matched French general population and by survivors. Using a clustering method, siblings were categorized into 3 groups depending on their level of QoL's scores and factors likely to be linked with these clusters were explored with multivariate analyses.
Results
We included 689 brothers and sisters (313 minors, 376 adults) and the mean time from diagnosis was 13.2 ± 6.6 years. Minor siblings reported higher QoL scores than general population (p < 0.001), but a lower score for relationship with family than survivors (p < 0.001). In adult siblings, Mental Component Summary score was lower than general population (p < 0.001). Level of siblings' QoL was linked with female gender, but no association was found with cancer‐related factors.
Conclusion
Brothers and sisters expressed a divergent perception of their long‐term QoL depending on their age. To minimize the impact from childhood to adulthood, long‐term attention should also be paid to siblings, often referred as “forgotten children”.
Years after diagnosis, brothers and sisters reported a different perception of their Quality of Life (QoL) according to their age, suggesting a deterioration in adulthood compared to their peers. Being female was associated with the lowest QoL level, but no association was found with cancer‐related factors.
Background
Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of ...DSD discovery.
Design/methods
All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed.
Results
Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age.
Conclusion
DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.
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