Tocilizumab for the treatment of paraneoplastic inflammatory syndrome associated with angiomatoid fibrous histiocytoma

Angiomatoid fibrous histiocytoma (AFH) is a rare sarcoma affecting children and young adults, with rare (1%) metastatic recurrence1.Fanburg-Smith J.C. Miettinen M. Angiomatoid "malignant" fibrous histiocytoma: a clinicopathologic study of 158 cases and further exploration of the myoid phenotype.http://www.ncbi.nlm.nih.gov/pubmed/10571514Hum Pathol. 1999; 30: 1336-1343doi:10.1016/S0046-8177(99)90065-5Google Scholar and driven by different gene fusions (EWSR1-ATF1, FUS-ATF1 and EWSR1-CREB1, the latter being the most common).2.Antonescu C.R. Dal Cin P. Nafa K. et al.EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma.http://www.ncbi.nlm.nih.gov/pubmed/17724745Genes Chromosomes Cancer. 2007; 46: 1051-1060doi:10.1002/gcc.20491Google Scholar Paraneoplastic inflammatory syndrome (PIS) is frequently associated with AFH: the EWSR1-CREB1 translocation involves CREB1, a transcription factor which binds to the interleukin 6 (IL6) promoter region.3.Akiyama M. Yamaoka M. Mikami-Terao Y. et al.Paraneoplastic syndrome of Angiomatoid fibrous histiocytoma may be caused by EWSR1-CREB1 Fusion-induced excessive interleukin-6 production.http://www.ncbi.nlm.nih.gov/pubmed/26165403J Pediatr Hematol Oncol. 2015; 37: 554-559doi:10.1097/MPH.0000000000000390Google Scholar Whether the EWSR1-ATF transcript can activate the IL6 gene similarly is unknown. We report the case of a 53-year-old male patient with bone and lymph node recurrence of an AFH of the left thigh, 18 months after surgery of the primary tumour. He presented with an 8-month history of left sciatica, fatigue, weight loss, fever and severe cough. RNA sequencing confirmed the EWSR1-ATF1 translocation and high expression of IL6 mRNA (figure 1A). C reactive protein (CRP) was 338 mg/L, and plasmatic IL6 more than six times the upper limit value (figure 1B,C). Based on the previous experience with a non-humanised anti-IL6 antibody, a treatment with the anti-IL6 monoclonal antibody, tocilizumab (8 mg/kg/2 weeks for 1 month, then every 3 weeks) provided a spectacular improvement of symptoms: after only two infusions, fever and cough completely regressed, CRP and IL6 normalised (figure 1B,C). The PET-scan evaluation after three infusions showed a complete metabolic response (figure 1D) but morphological progression, required additional systemic therapy. Adriamycin, pazopanib, ifosfamide and trabectedin were given sequentially, in combination with tocilizumab, yielding a progression-free survival of 2, 9, 2, and 1 month, respectively. The patient eventually died from a bacterial infection 24 months after the initiation of tocilizumab, in a context of disease progression. The impact of anti-IL6 on AFH growth remains unclear. This patient had a complete metabolic response on PET (maximal SUV (standardized uptake value) from 7.6 to 3.2) but a morphological progression (+38%). The role of IL6 as a growth factor in this case is unclear: IL6 was reported to act as an intracrine growth factor in renal cell carcinoma, preventing anti-IL6 antibody to inhibit the signal.4.Alberti L. Thomachot M.C. Bachelot T. et al.IL-6 as an intracrine growth factor for renal carcinoma cell lines.http://www.ncbi.nlm.nih.gov/pubmed/15252833Int J Cancer. 2004; 111: 653-661doi:10.1002/ijc.20287Google Scholar Treatment with tocilizumab was overall well tolerated, though a contribution to the lethal infection cannot be excluded, as reported in patients with rheumatoid arthritis. Interestingly, while the patient had disease progression despite 4 lines of therapy, overall survival was 24 months, beyond what is reported for advanced sarcoma with inflammatory syndrome and primary progression to doxorubicin. Long-term control of PIS more than a direct antineoplastic effect of tocilizumab possibly contributed to the 24-month survival. A partial metabolic response and remission of IL6-induced PIS with tocilizumab was previously reported in a case of a paediatric metastatic AFH with an EWS-CREB1 fusion.5.Potter S.L. Quintanilla N.M. Johnston D.K. et al.Therapeutic response of metastatic angiomatoid fibrous histiocytoma carrying EWSR1-CREB1 fusion to the interleukin-6 receptor antibody tocilizumab.http://www.ncbi.nlm.nih.gov/pubmed/29932283Pediatr Blood Cancer. 2018; 65 (e27291)doi:10.1002/pbc.27291Google Scholar Treatment with tocilizumab led to remission of severe IL6-induced PIS associated with metastatic AFH, where IL6 overproduction is likely related to the oncogenic fusion involving transcription factors regulating IL6. The contribution of this anti-IL6 antibody to clinical tumour growth factor in AFH remains to be established, and will be further explored. The authors especially would like to thank Hoffmann-LaRoche for providing Tocilizumab (ROACTEMRA) for the patient.