Integrated analysis of long‐term growth and bone development in pediatric and adolescent patients receiving bevacizumab

Müller, Hermann L.; Merks, Johannes H. M.; Geoerger, Birgit; Grill, Jacques; Hargrave, Darren; Bender, Julia Glade; Gururangan, Sridharan; Navid, Fariba; Johnston, Michael; Bachir, Jeanette; Elze, Markus C.; Fürst‐Recktenwald, Sabine

doi:10.1002/pbc.27487

Cited by 5 publications

(4 citation statements)

References 26 publications

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“…Gerber et al [10] showed that VEGF-mediated capillary invasion is an important signal that regulates growth plate morphogenesis and triggers cartilage remodeling. However, Müller et al [20] observed no negative effects of bevacizumab on growth and development in pediatric and adolescent patients receiving bevacizumab and chemotherapy, which has been used in various types of cancer, compared with those receiving chemotherapy alone. We are unaware of any study showing the intra-articular effect of bevacizumab on joint development in children.…”

Section: Discussionmentioning

confidence: 99%

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Mert

Bılgıç

Şenol

et al. 2023

Clin Orthop Relat Res

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Background Hemophilic arthropathy can cause recurrent hemarthroses and severe damage to the synovium and articular cartilage. Previous studies have shown that vascular endothelial growth factor (VEGF) plays an essential role in neoangiogenesis. Bevacizumab, a monoclonal VEGF inhibitor, is used clinically to prevent angiogenesis. However, its effects on hemophilic arthropathy are unknown. Questions/purposes Using a hemophilic arthropathy rabbit model, we asked: Does an intra-articular injection of bevacizumab (1) inhibit VEGF, (2) decrease signal intensity in dynamic contrast-enhanced MRI (DCE-MRI) as an assessment of capillary permeability and neoangiogenesis, (3) reduce cartilage damage, (4) reduce synovial changes, and (5) affect macroscopic changes during the development of hemophilic arthropathy? Methods Twenty-five male New Zealand rabbits were divided into four groups. Eight knees from four rabbits were used as the control group. We used an established animal model for hemophilic arthropathy in the remaining 21 rabbits. Animals were assigned randomly to three groups with seven rabbits in each group. One group was used to establish mild arthropathy, and the other two were used to establish severe arthropathy. Autologous blood from the rabbits’ ears was injected into the right and left knees twice per week for 8 weeks to represent mild arthropathy and for 16 weeks to represent severe arthropathy. In the mild arthropathy group, bevacizumab was injected into the right knee once every 2 weeks. Bevacizumab was injected into the right knee of rabbits in one of the severe arthropathy groups once every 2 weeks for 16 weeks, and intra-articular bevacizumab injections were administered to the right knees of rabbits in the other severe arthropathy group once every 2 weeks after the eighth week. An equal volume of 0.9% saline was injected into the left knee of rabbits in all arthropathy groups. To explore the efficacy of bevacizumab, joint diameters were quantitatively measured, and cartilage and synovial changes were examined. Degeneration of articular cartilage was evaluated with the semiquantitative Osteoarthritis Research Society International grading system. Synovial damage was analyzed with a semiquantitative microscopic scoring system. In addition, we evaluated perfusion and angiogenesis using DCE-MRI (quantitative signal intensity changes). Immunohistochemical testing was used to measure VEGF levels (analyzed by Western blotting). Results Intra-articular bevacizumab treatment inhibited VEGF in our rabbit model of hemophilic arthropathy. VEGF protein expression levels were lower in the mild arthropathy group that received intra-articular bevacizumab (0.89 ± 0.45) than the mild arthropathy control group (1.41 ± 0.61) (mean difference -0.52 [95% CI -0.898 to -0.143]; p = 0.02). VEGF levels were lower in the severe arthropathy group that received treatment for 16 weeks (0.94 ± 0.27) than in the control knees (1.49 ± 0.36) (mean difference -0.55 [95% CI -0.935 to -0.161]; p = 0.01). In the severe arthropathy group, the Osteoarthritis Research Society International score indicating cartilage damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than in the control group (median 17 [range 13 to 18] versus 18 [range 17 to 20]; difference of medians 1; p = 0.02). Additionally, the scores indicated synovial damage was lower in the group that received intra-articular bevacizumab treatment from the beginning than the control group (median 5 [range 4 to 9] versus 9 [range 8 to 12]; difference of medians 4; p = 0.02). The mean of mean values for signal intensity changes was higher in the nontreated severe groups than in the group of healthy knees. The signal intensity changes were higher in the severe arthropathy control groups (Groups BC and CC) (median 311.6 [range 301.4 to 361.2] and 315.1 [range 269.7 to 460.4]) than in the mild arthropathy control group (Group AC) (median 234.1 [range 212.5 to 304.2]; difference of medians 77.5 and 81, respectively; p = 0.02 and p = 0.04, respectively). In the severe arthropathy group, discoloration caused by hemosiderin deposition in the cartilage and synovium was more pronounced than in the mild arthropathy group. In the severe arthropathy group treated with intra-articular bevacizumab, joint diameters were smaller than in the control group (Group BT median 12.7 mm [range 12.3 to 14.0] versus Group BC median 14.0 mm [range 13.1 to 14.5]; difference of medians 1.3 mm; p = 0.02). Conclusion Hemarthrosis damages the synovial tissues and cartilage in the knees of rabbits, regardless of whether they are treated with intra-articular bevacizumab. However, intra-articular injection of bevacizumab may reduce cartilage and synovial damage in rabbits when treatment is initiated early during the development of hemophilic arthropathy. Clinical Relevance If the findings in this study are replicated in larger-animal models that consider the limitations of our work, then a trial in humans might be appropriate to ascertain whether intra-articular injection of bevacizumab could reduce cartilage damage and synovial changes in patients with hemophilia whose hemarthroses cannot otherwise be controlled.

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Section: Discussionmentioning

confidence: 99%

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Mert

Bılgıç

Şenol

et al. 2023

Clin Orthop Relat Res

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“…14 As seen in preclinical studies, long-term use of bevacizumab has the potential to lead to growth plate or epiphyseal abnormalities, although it has yet to be reported in pediatric clinical studies, likely because bevacizumab has yet to be used in a sustained way. 15 Molecular characterization has further elucidated our understanding of pLGG with the majority of pLGG harboring driver mutations in the ratsarcoma virus/mitogen-activated protein kinase pathway. 5 With the advent of molecular data regarding BRAFV600E and BRAF fusion mutations, mitogen-activated protein kinase kinase inhibitors have emerged as an adjunct therapy for pLGG.…”

Section: Discussionmentioning

confidence: 99%

“…The most reported side effects of bevacizumab in the literature include proteinuria, hypertension, epistaxis, and fatigue 14. As seen in preclinical studies, long-term use of bevacizumab has the potential to lead to growth plate or epiphyseal abnormalities, although it has yet to be reported in pediatric clinical studies, likely because bevacizumab has yet to be used in a sustained way 15. Molecular characterization has further elucidated our understanding of pLGG with the majority of pLGG harboring driver mutations in the rat-sarcoma virus/mitogen-activated protein kinase pathway 5.…”

Section: Discussionmentioning

confidence: 99%

Single-agent Bevacizumab in the Treatment of Symptomatic Newly Diagnosed and Recurrent/Refractory Pediatric Cervicomedullary Brainstem Low-grade Gliomas: A Single Institutional Experience

Sridhar

Paul

Yeh-Nayre

et al. 2022

Journal of Pediatric Hematology/Oncology

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Bevacizumab-based therapies have been utilized as single or combination therapy of refractory/recurrent pediatric low-grade gliomas. Its efficacy for symptomatic cervicomedullary low-grade gliomas (cmLGGs) in the upfront and the recurrent setting is less known. We report our retrospective single institutional experience from 2015 to 2021 with single-agent bevacizumab for symptomatic cmLGG. Six consecutive patients (4 female, ages 2 to 12 y) with newly diagnosed (n=3) and recurrent/refractory (n=3) symptomatic nondisseminated cmLGG (5/6 biopsy-proven, 2 BRAFV600E, 2 BRAF-KIAA1549) were treated with single-agent bevacizumab. All demonstrated radiographic response most pronounced on post-gadolinium T1-weighted magnetic resonance imaging (2 complete, 4 partial) at a median of 8 weeks (range: 2 to 12 wk). Clinical response was seen in all patients with improvement in cranial nerve abnormalities (3 recurrent/refractory, 1 newly diagnosed), strength (2 recurrent/refractory, 2 newly diagnosed), pain (2 recurrent/refractory), and anorexia (1 newly diagnosed). Four patients (2 recurrent/refractory, 2 newly diagnosed) experienced disease progression on subsequent adjunct therapies, 2 of which (the 2 newly diagnosed patients) are currently being rechallenged. At a mean follow-up of 7 months, all patients are clinically stable without disease progression. Single-agent bevacizumab may be effective in the management of symptomatic newly diagnosed and recurrent/refractory cmLGG and warrants further evaluation in a clinical trial setting.

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“…As some of these agents move forward and are being evaluated in front line studies, there is a greater need to continue growth plate monitoring (96,97). Although a pooled analysis of children receiving bevacizumab showed no negative effects on growth velocity, height, or body mass index (98), longer followup of patients treated with these drugs is needed to determine long term effects on growth and development.…”

Section: Linear Growth With Imatinib and Other Tkismentioning

confidence: 99%

Opportunities and Challenges in Drug Development for Pediatric Cancers

et al. 2021

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The use of targeted small-molecule therapeutics and immunotherapeutics has been limited to date in pediatric oncology. Recently, the number of pediatric approvals has risen, and regulatory initiatives in the United States and Europe have aimed to increase the study of novel anticancer therapies in children. Challenges of drug development in children include the rarity of individual cancer diagnoses and the high prevalence of difficult-to-drug targets, including transcription factors and epigenetic regulators. Ongoing pediatric adaptation of biomarker-driven trial designs and further exploration of agents targeting non-kinase drivers constitute high-priority objectives for future pediatric oncology drug development. Significance: Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies for children with cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy. However, unique approaches are necessary to study novel therapies in children that take into account low patient numbers, the pediatric cancer genomic landscape and tumor microenvironment, and the need for pediatric formulations. It is also critical to evaluate the potential for unique toxicities in growing hosts without affecting the pace of discovery for children with these life-threatening diseases.

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Integrated analysis of long‐term growth and bone development in pediatric and adolescent patients receiving bevacizumab

Cited by 5 publications

References 26 publications

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

What is the Effect of Bevacizumab on Cartilage and Synovium in a Rabbit Model of Hemophilic Arthropathy?

Single-agent Bevacizumab in the Treatment of Symptomatic Newly Diagnosed and Recurrent/Refractory Pediatric Cervicomedullary Brainstem Low-grade Gliomas: A Single Institutional Experience

Opportunities and Challenges in Drug Development for Pediatric Cancers

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