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. 2022 Jan 11;6(1):72-81.
doi: 10.1182/bloodadvances.2021005278.

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials

Yannis K Valtis  1 , Kristen E Stevenson  2 , Andrew E Place  3   4 , Lewis B Silverman  3   4 , Lynda M Vrooman  3   4 , Giacomo Gotti  3   4 , Andrew M Brunner  5 , Mary Nauffal  6 , Daniel J DeAngelo  7 , Marlise R Luskin  7
Affiliations

Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials

Yannis K Valtis et al. Blood Adv. .

Abstract

Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Overview of DFCI AYA ALL Treatment protocols. (A) Earlier patients were enrolled on parallel pediatric 00-001 (2000-2004) and adult 01-175 (2002-2008) trials while later patients were enrolled on parallel pediatric 05-001 (2005-2011) and adult 06-254 (2007-2011) trials. (B) Breakdown of patients according to treatment protocol, age, and asparaginase formulation. 1Intention-to-treat postinduction asparaginase formulation. Patients who did not receive postinduction asparaginase are excluded from this table. 2Cumulative incidence (death included as competing risk). CNS , central nervous system; Dx, diagnosis; Fx, fracture.
Figure 2.
Figure 2.
Incidence over time of ON and fracture in 367 AYA patients with ALL. Median time to event was 1.6 years for ON (A) and 1.4 years for fracture (B).
Figure 3.
Figure 3.
Probability of ON according to risk group. Probability of ON by age group (A) and by treatment protocol (B). Early-generation protocols 00-001 and 01-175 used E. coli asparaginase, whereas late-generation protocols 05-001 and 06-254 mostly used pegaspargase.
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