Osteonecrosis in children and adolescents with acute lymphoblastic leukemia: a therapeutic challenge

Abstract

Osteonecrosis (ON) represents one of the most common and debilitating sequelae of antileukemic treatment in children and adolescents with acute lymphoblastic leukemia (ALL). Systematic screening strategies can focus on early detection and intervention to prevent ON from progressing to stages associated with pain and functional impairment. These strategies hold promise for reducing ON-associated morbidity without the risk of impairing leukemia control. Herein, we critically reviewed clinical data on pharmacological, nonpharmacological/nonsurgical, and surgical (including cellular) treatment options for ON, which are covered in the literature and/or are conceivable based on the supposed underlying ON pathophysiology. Prevention of ON progression is of paramount importance, and attempts seem to be more effective in early (precollapse) disease status than in late-stage (collapse) ON. Based on the results of ongoing prospective magnetic resonance imaging screening studies, which will hopefully identify those patients with a high risk of ON progression and debilitating sequelae, prospective interventional studies are urgently needed. Although there is still a lack of high-quality studies, based on currently available data, core decompression surgery combined with cellular therapies (eg, employing mesenchymal stem cells) appears most promising for preventing joint infraction in children at high risk of developing late-stage ON.

Figure 1.

Exemplary patient from the OPAL trial. On coronal images of knees, short tau inversion recovery images (top row) show diffuse hyperintense inhomogeneous signals, and T1-weighted images (bottom row) show diffuse hypointense signals revealing extensive leukemic infiltration of bone at diagnosis. At the 6-month follow-up examination, the hyperintense signal in short tau inversion recovery decreased and the hypointense signal in T1 increased toward normal appearance. At 9 months into treatment, MRI shows asymptomatic lesions in the metaphyses, which shows spontaneous regression beginning at 12 months into treatment.

Figure 2.

Overview of conceivable pharmacological, nonpharmacological, nonsurgical, and surgical (combined with cellular therapies) potential prevention and intervention options in children and adolescents with ALL. (A) The illustrations depict examples according to the association research circulation osseous (ARCO) classification for the hip joints. Screening of underlying coagulopathies and hyperlipidemia to prevent progression of early-stage ON and eventual compensation of vitamin D deficiency may be considered. The colored arrows indicate in which treatment phases and ON stages the depicted prevention strategies might be effective. (B) Overview of conceivable preventive pharmacological interventions in children and adolescents with ALL assigned to the different phases of the Berlin Frankfurt Muenster (BFM) therapy backbone and the cytostatic drugs and the treatment-related metabolic side effects. CPM, cyclophosphamide; HR, high risk; MP, mercaptopurine; MTX, methotrexate; NWB, non–weight-bearing; SR, standard risk; TG, thioguanine; THA, total hip arthroplasty.