Modifiable Determinants of Osteonecrosis in Children and Adolescents with Acute Lymphoblastic Leukemia and Functional Outcome

Summary

With the marked improvement in outcome of childhood, major morbidities remain major concerns affecting the patients` quality of life. One of the major morbidities is bone osteonecrosis affecting major weight bearing joints, causing pain and necessitating surgical intervention and therapy modifications. We aimed to study the incidence rate of early development of osteonecrosis in the major weight bearing joints and to study the main risk factors with the aim of modification of some risk factors such has hyperlipidemia and/or sex hormone with LHrH analogues if incriminated in the development of such major morbidity. The relation between hyperlipidemia, steroid regimens and the alteration of sex hormones with the incidence of osteonecrosis needs to be studied in concomitantly in the same patient and put a possible causative and modifiable etiology for the development of osteonecrosis in such patient

Osteonecrosis is one of the most common and debilitating therapy-related side effects of anti-leukemic treatment and can adversely affect long-term quality of life. There is high incidence of osteonecrosis in different major joints during treatment of childhood ALL reaching 35-67% (Kunstreich M K. S., 2016). In a questionnaire based screening of osteonecrosis in childhood ALL, the majority of patients had multifocal ON, most commonly affected joints were hips (34%), knees (32%), shoulders (14%) and ankles (10%) (Amin NL, 2017).

Many risk factors have been incriminated for the development of osteonecrosis in childhood ALL including age of patients, gender (Strauss AJ, 2001), steroids regimen (McAvoy S, 2010) used and some germline polymorphism linked to pharmacodynamics of chemotherapy, bone metabolism, adipogenesis, glutamate signaling pathway, and mesenchymal stem cell differentiation (Kunstreich M K. S., 2016).

The high impact of age on the development of osteonecrosis poses several possible unsolved issues regarding the cause of high incidence of osteonecrosis above the age of 10 years, and whether it is related to bone changes in this age or the impact of sex hormones (Lackner H, et al.,2005).

Thus we are aiming at evaluating the frequency of symptomatic and asymptomatic osteonecrosis around the hips, knees and ankles in children with acute lymphoblastic leukemia and its impact on pain and functional activity and To study the impact of lipid profile of the occurrence of osteonecrosis in children with ALL

A prospective Observational study will be conducted

Sampling methods : consecutive sampling

Study duration: 12 months

Study type: prospective cross-sectional study

Study setting: Hematology and oncology clinic at Children Hospital –Ain shams university

Inclusion Criteria: Children more than the age of five with newly diagnosed acute lymphoblastic leukemia

Sample size: Based on the results of Kunstreich et al., 2016, with the prevalence of osteonecrosis ranging from 1.7 to 17% , alpha error 5% and power of study 80%, the required sample size is 50 patients.The program for sample size calculation is STATA 10

Methods

2 points Evaluation will be performed: One time point is week 1-3 and Second time point is after week 9-11 of maintenance

Clinical Data:

Patients Characteristics: Age, gender, family history of bone disease or thrombotic disorders or malignancies.

Examination data: Anthropometric data, pain score

Disease Related Data:  type of ALL, WBC count, protocol use, type of steroids used

Laboratory data:

Hematologic Evaluation: blood picture

Metabolic Evaluation including serum calcium, Phosphorus, Alkaline phosphatase, vitamin D level complete fasting  lipid profile

Hormonal Evaluation: Follicular stimulating hormone (FSH) and Luteinizing hormone (LH)

Radiologic Evaluation: Plain Xray and MRI hips, knees and ankles

The Ficat and Arlet classification uses a combination of plain radiographs, MRI, and clinical features to stage avascular necrosis of the femoral head excluding bone scan (Ficat RP, 1985) divided into Stage 0: normal plain radiograph and MRI and negative clinical symptoms, Stage I: plain radiograph with normal findings or minor osteopenia,  MRI showing oedema with  Clinical symptoms manifested as pain typically in the groin; Stage II with  mixed osteopenia and/or sclerosis and/or subchondral cysts, without any subchondral lucency on plain radiograph, MRI: geographic defect with pain and stiffnesss.; Stage III: plain radiograph  and MRI showing crescent sign and eventual cortical collapse with Clinical symptoms of pain and stiffness+/- radiation to knee and limp and Stage IV: plain radiograph and MRI of end-stage with evidence of secondary degenerative change and Clinical symptoms of pain and limp.

Mitchell classification of avascular necrosis is based on MRI signal characteristics within the center of the lesion on T1 and T2-weighted images. The lesion is classified into four stages with stage (A) representing early disease and stage (D) representing late disease. However, the signal intensity of more than one stage can be found in a single lesion (Mitchell et al, 1987). Stage A T1: hyperintense, T2: intermediate and Signal analogous to that of fat; Stage B T1: hyperintense, T2: hyperintense and Signal analogous to that of subacute blood; Stage C T1: hypointense, T2: hyperintense and Signal analogous to that of fluid/oedema and Stage D T1 hypointense, T2 hypointense and Signal analogous to that of fibrosis.

ALL procedures will be done after approval of Ethical committee of Ain shams university and an informed consent will be taken from patients or legal guardians after explaining all study procedures