Abstract
FGFR tyrosine kinase inhibitors (TKIs) are increasingly being used off label in pediatrics. Long term safety data is limited, and serious toxicities unique to pediatrics may emerge. In a retrospective analysis of patients<18 years of age with recurrent/refractory FGFR altered gliomas treated with FGFR TKIs at MSKCC (n=7), we observed slipped capital femoral epiphyses (SCFE) in 3 of 7 patients along with increased linear growth velocity. Clinicians should closely monitor bone health and have a low index of suspicion for serious orthopedic complications including SCFE and inform patients of related risks as part of consent when treating with FGFR TKIs.
Keywords: fibroblast growth factor receptor inhibitor, slipped capital femoral epiphyses, skeletal toxicity
FGFR signaling plays key roles in regulating chondrogenesis, osteogenesis, bone and mineral homeostasis.1 In adults, presumably owing to complete/near complete skeletal/cartilage maturation and diminished role of FGFR signaling, skeletal side effects of FGFR TKIs were not reported. In contrast, the risks of FGFR inhibition during critical periods of growth in skeletally immature patients are unknown.
We previously reported one patient who developed slipped capital femoral epiphyses (SCFE) on treatment with a selective FGFR1–3 TKI,2 but deemed this adverse event unrelated to study drug. With longer follow up in an expanded cohort of patients treated with different selective FGFR TKIs (n=7), we observed that all patients experienced a significant increase in linear growth velocity and two additional patients developed SCFE following 40 months and 5 months on treatment (see Figure 1).2 Disease details and bony complications for all 7 patients are provided in table 1.
Graph depicting height in centimeters on the y axis versus weeks post start of FGFR TKI treatment for subject 1 (A). Postero-anterior PA radiograph of the left hip is normal with Klein’s line drawn depicting small amount of epiphysis projecting lateral to the line (normal) (B). A radiograph obtained 6 weeks later with identical positioning reveals the severe “slip” of the femoral epiphysis (between arrows) with respect to the metaphysis (C). Summary of treatment course from start of FGFR TKI treatment for subject 1 (D). Graph depicting height in centimeters on the y axis versus weeks post start of FGFR TKI treatment for subject 2 (E). Radiographic evidence of osteochondritis dissecans involving the typical position of the lateral aspect of the medial femoral condyle on PA (arrows) (F) and lateral radiographs of the right knee (arrows) (G). The patient later was diagnosed with slipped capital femoral epiphyses (SCFE). Frog-leg lateral view of the right femoral head shows the epiphysis having fallen posteriorly. The appearance has been likened to an ice cream falling off a cone. There is slight widening of the physis (arrows) (H). Normal contralateral side for reference (I). Summary of treatment course from start of FGFR TKI treatment for subject 2 (J). Graph depicting height in centimeters on the y axis versus weeks post start of FGFR TKI treatment for subject 3 (K). Orthopedic pinning to stabilize the proximal femurs bilaterally (L). PA radiograph suggests widening and irregularity of the physis (M). The lateral view confirms SCFE (N). The contralateral femur suggests mild widening of the physis raising suspicion for SCFE (O) – particularly in the context of the right sided diagnosis. Summary of treatment course from start of FGFR TKI treatment for subject 3 (P).
Table 1.
Disease details and bony complications for patients treated with FGFR inhibitors
| Subject | Age at start of treatment/Sex | Tumor type | FGFR alteration | Duration of treatment (months) | Height percentile/Z score at start of treatment | Height percentile/Z score at end of treatment | Bony complications |
|---|---|---|---|---|---|---|---|
| 1 | 26m/F | optic pathway pilomyxoid astrocytoma | FGFR1-TACC1 fusion | 9 | 57/0.17 | 94/1.53 | None |
| 2 | 8y/F | optic pathway pilomyxoid astrocytoma | FGFR1 mutations (V592M, K687E) | 9 | 72/0.59 | 98/2.1 | SCFE, avascular necrosis of hip, non-traumatic fractures |
| 3 | 14y/M | rosette-forming low grade glioneuronal tumor |
FGFR3-TACC3 fusion | 40 | 83/0.97 | >99/3.4 | SCFE, osteochondritis dissecans, bilateral coxa valga deformity |
| 4 | 13m/M | spinal cord (T1–T8) high grade glioma | FGFR1 mutations (V592M, K687E) | 12 | 5/-1.65 | 47/-0.05 | None |
| 5 | 8y/M | cerebellar glioblastoma | FGFR1 N577K | 5 | 9/-1.32 | 17/-0.96 | None |
| 6 | 12y/M | Diffuse brainstem glioma | FGFR2-VPS35 fusion | 5 | 30/-0.53 | 69/0.49 | SCFE, non-traumatic fractures |
| 7 | 18y/F | High grade glioma, IDH wild type | FGFR3-TACC3 fusion | 2 | 15/-1.03 | 18/0.9 | None |
Abbreviations: SCFE, slipped capital femoral epiphyses; FGFR, Fibroblast growth factor receptor; TACC, Transforming acidic coiled-coil
FGFR3 is a negative regulator of endochondral bone growth. The skeletal phenotype of Fgfr3−/− mice is characterized by elongated long bones (femur) and FGFR TKI treatment resulted in cartilage dysplasia/abnormalities in the femoral head/neck and acetabulum, limping and soft tissue mineralization.1 The murine phenotype is recapitulated in clinical reports of germline FGFR3 aberrations in humans. Germline homozygous loss-of-function mutations in FGFR3 result in a skeletal overgrowth syndrome (CATSHL syndrome) characterized by tall stature and severe skeletal abnormalities leading to inability to walk.3 Conversely, germline FGFR3 gain of function alterations are described in achondroplasia and FGFR TKIs are being investigated at lower doses to improve linear bone growth in these patients (NCT04265651). In conjunction with the preclinical toxicities and established genotype phenotype correlations, our clinical observations in patients treated with two separate FGFR selective TKIs (Debio1347 and Erdafitinib which equally inhibit wild type and mutant FGFR) provide a strong link between FGFR signaling disruption and the development of SCFE.
Children presenting with SCFE who are under 10 or over 16 years of age with normal growth are considered to have an atypical presentation.4 Our patients were 9 years, 17 years and 13 years of age when SCFE was diagnosed. Predisposing features that weaken the physeal plate include widening of physis associated with rapid growth acceleration (observed in all our patients), obesity and endocrine/metabolic disorders causing abnormal growth and mineralization of cartilage.5 Two of our patients were obese while the third was a tall thin adolescent. Hyperphosphatemia, a class specific toxicity of FGFR TKIs, and observed in all patients, causes bone resorption and may have contributed to SCFE. Prolonged exposure (all subjects received >4 months of treatment) appears necessary and likely explains the paucity of bony toxicities reported to date from ongoing pediatric (NCT03210714, NCT05222165) and adult basket trials,6,7 where median TKI exposure may be limited by early disease progression.
The long term complications of SCFE include osteonecrosis of the femoral head, chondrolysis and premature onset osteoarthritis with need for reconstructive surgery.8 Our findings raise concerns regarding the potential feasibility of prolonged FGFR TKI therapy in skeletally immature pediatric patients treated on ongoing clinical trials and off-label therapy. Providers should closely monitor bone health and inform patients and families of related risks as part of informed consent. Specific recommendations include close attention to growth velocity and clinical symptoms of hip/groin/knee pain along with serial imaging surveillance to assess bilateral hips (serial radiographs of both antero-posterior and frog leg lateral views) for SCFE.
ACKNOWLEDGEMENT:
Investigational drug Debio1437 was provided by Debiopharm International SA under Single Patient Use (SPU) protocols. This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant P30 CA008748. We would like to thank Dr. Neerav Shukla and Dr. Julia Glade Bender along with members of the Pediatric Translational Medicine Program at MSK Kids. We would like to thank Dr. Stephen Gilheeney for patient care and Joe Olechnowicz for editorial assistance.
Funding:
Investigational drug Debio1437 was provided by Debiopharm International SA under Single Patient Use (SPU) protocols. This work was funded in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the National Cancer Institute Cancer Center Core Grant P30 CA008748.
Abbreviations:
- FGFR
Fibroblast growth factor receptor
- TKI
Tyrosine kinase inhibitor
- CATSHL
camptodactyly, tall stature, scoliosis, and hearing loss syndrome
- SCFE
Slipped capital femoral epiphysis
Footnotes
Conflict of Interest Statement: Dr. Karajannis reports active consultant agreements with AstraZeneca, CereXis, Recursion and QED Therapeutics (personal fees received). Dr. Dunkel reports active consultant agreements with Astra Zeneca, Bristol-Myers Squibb, and Pyramid (personal fees received). Dr. Farouk Sait reports completed consultant agreements with AstraZeneca (personal fees received) and QED Therapeutics
Contributor Information
Sameer Farouk Sait, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York..
Cheryl Fischer, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York..
Zoltan Antal, Department of Endocrinology, Memorial Sloan Kettering Cancer Center, New York, New York..
Krisoula Spatz, Department of Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York..
Daniel E. Prince, Department of Orthopedics, Memorial Sloan Kettering Cancer Center, New York, New York.
Katarzyna Ibanez, Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York..
Gerald G. Behr, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Ira J. Dunkel, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Matthias A. Karajannis, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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