DISCUSSION

Our study on osteonecrosis was carried out on one of the largest cohort of children and adolescents followed for leukemia, and it was the first radiological study conducted in pediatrics on such a population. We demonstrated that osteonecrosis in the follow-up of childhood acute leukemia was a rare complication (2.5%) except for children over 10 years at the time of diagnosis (10.6%). Early access to MRI allowed characterization of the lesions which were most often multifocal at diagnosis. Moreover, the occurrence of osteonecrosis had a global and rapid negative impact on quality of life which lasted in adulthood.
The incidence of symptomatic ON remained similar (2.8% in 2019 vs 2.5%) 12 in comparison with the L.E.A. 2013 study but the current size of the cohort made the exploration of the risk factors of occurrence and consequences on QoL more relevant.
We confirmed that being a female older than 10 years and suffering from ALL increased the risk of ON 8,12,27,28. The absence of ON in AML patients who did not undergo SCT could be explained by shorter treatment not involving corticosteroid therapy. Whereas an hormonal role on the occurrence of ON has been described14 in literature, the lack of significance of the gender in the transplanted population could be explained by two factors: the major role of overall metabolic disturbances induced by the transplant and the possible lack of vigilance for post-transplant hormonal substitution in female for the oldest patients. We also confirmed in our large cohort the impact of chronic GVHD12. We did not evaluate in our current cohort the cumulative steroid dose because its role in ON occurrence was well described in various studies but we can speculate that the negative impact of an history of relapse could be in part due to an higher cumulative steroid dose 5,9,10.
Furthermore our study showed for the first time on an homogeneous population that children who received treatment against leukemia, presented with multifocal joint involvement (mainly weight-bearing joints) at ON diagnosis while in other systemic pathologies, such as sickle cell anemia, also known for the frequent occurrence of osteonecrosis, involvement is predominantly unifocal (80% of cases)29. This is probably due to corticosteroid therapy, since Kuhlen et al has shown it in adult population30 and Krez et al also showed that a high cumulative dose of glucocorticoids was associated with a risk of multifocal disease in patients with different underlying conditions like systemic lupus erythematosus 31.
We also described the continuing negative impact of the occurrence of osteonecrosis on physical, social, and psychological scores. The absence of changes in QoL between the onset of ON and the last assessment suggests that QoL was permanently impaired as soon as ON occurred. The weak therapeutic arsenal, represented mainly by chirurgical joint prosthesis 32, could explain the lack of possible improvement in the quality of life in these patients.
Finally, our study gave new insights about radiological presentation of ON in the context of leukemia. The widespread access to MRI since 2009 has allowed a representative description of more than 70% of patients with osteonecrosis. We chose to exclude the re-reading of the images of the patients who benefitted from MRI with a delay longer than 6 months (10%) to avoid the risk of lesion modification over time. Because a minor stage change for the same articulation on the follow-up MRI was found in only 20% of patients, we could probably include them in a further study. The centralized blinded proofreading by two radiological experts was a strength of our study. They could correct the diagnosis of osteonecrosis for 3 patients whose MRI lesions were osteochondritis, an isolated diaphyseal infarction and an inflammatory arthritis. The rare disagreements during the re-reading of the MRI have always been linked to images that were difficult to interpret due to a lack of sequences, when the measurement of the affected joint surface was very close to 30%.
We found mainly severe multifocal radiological damages probably because we included only symptomatic ON. We questioned here the interest to perform systematically a whole joint MRI for searching other damaged but asymptomatic joints in the aim to detect milder lesions and preserve the joint destruction. The radiological diagnosis of these asymptomatic joints could then result in a need for restrictive care like discharge by crutch or wheelchair, balneotherapy and physiotherapy sessions while the patient is not in pain. The benefit of this early diagnostic imaging remains to be demonstrated by a novel study. Our study also raised the issue to perform systematically whole weight bearing joint MRI for children over 10 years old, especially for females with multiple sequelae. The radiological follow-up of these asymptomatic patients should be analyzed in a prospective study to find out whether they progress to regression of the MRI stage. Indeed, Inaba showed recently that MRI at the end of induction of ALL treatment could identify susceptible patients who could benefit of an extensive follow-up imaging and early medical intervention 33 but this study should be confirmed.
Our retrospective study had two main limits: the frequent absence of available MRI for the ON diagnosed before 2009 which limited the size of the study n°2 and the lack in the L.E.A registry of data of accurate information on medical intervention, the use of physiotherapy or discharge for the ON. We were not able to conclude that medical intervention has an impact by the retrospective nature of our study. Prospective data about treatment are essential to establish management recommendations in the future as well as biological insights. Since not all patients exposed to the same treatment will develop ON, we can assume that pathophysiological mechanisms are underpinned by genetic polymorphisms. Some studies go in this direction, with an impact of the nucleotide polymorphisms of the plasminogen activator inhibitor 1-gene, or glutamate receptor GRIN3A 34,35. The nested case control French GENLEA01 study (Genome-wide association studies GWAS identification of genetic factors affecting the occurrence of late side effects in childhood leukemia survivors from the L.E.A cohort) could help to solve these questions in the future.