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Case Reports
and therefore withdrawn one month later. At day +100 post HSCT the patient was clinically well with full donor chimerism on total BM and PB, as well as on lymphoid and myeloid subpopulations (Table 1). She is currently nine months after the third haplo HSCT and the patient remains in good clinical conditions and is infection-free. Based on emapalumab half-life, the patient has remained on anti-TB prophylaxis to mitigate the risk of reactivation until measurable levels of the drug were present.
Italy; 8Clinic of Infectious Diseases, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; 9Neuroradiology Unit, Head and Neck Department, IRCSS San Raffaele Scientific Institute, Milan, Italy; 10Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy; 11Swedish Orphan Biovitrum AG (Sobi), Basel, Switzerland and 12Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
*FT and VG contributed equally as co-first authors.
Correspondence:
MARIA ESTER BERNARDO - bernardo.mariaester@hsr.it
doi:10.3324/haematol.2020.255620
Disclosures: MPC is PI of the long-term follow up study sponsored by Orchard Therapeutics for patients treated with Strimvelis and AA is PI of clinical trials sponsored by Orchard Therapeutics.
VA is an employee of Sobi; CdM is consultant for Sobi.
Contributions: FT, VG followed the clinical course of the patient, collected data, analyzed results and wrote the paper; FB, FF, MM, VC, MD, MPC, ESF, CO followed the clinical course of the patient and collected data; ZK and SGu followed the patient before referral
to our Institution; SGa collected peripheral blood hematopoietic stem cells from the donors; MZ, CP and RM performed graft manipulation; BM performed chimerism analyses; CB and MB performed radiological evaluations; DMC performed fecal PCR for detection of Mycobacterium bovis; VA and CdM provided emapalumab as per CU, performed PK/PD emapalumab evaluations, critically read the manuscript and helped with scientific discussion; AA and FC critically revised the manuscript and helped with scientific discussion; MEB advised on the design the study, analyzed data and contributed to the final writing of the paper.
Acknowledgments: we are grateful to Ambra Corti for support in regulatory aspects of the study, and Manuela Gavina, Francesca Dionisio, Stefania Giannelli and Claudia Sartirana for technical support. We thank Emanuele Borroni for support with the mycobacteriology investigations.
References
1.Al-Salama ZT. Emapalumab: first global approval. Drugs. 2019; 79(1):99-103.
In conclusion, we report the case of a very fragile, heavily immunosuppressed patient affected by ADA- SCID who experienced GF after multiple HSCT in the presence of life-threatening infections including dissemi- nated TB, who was safely treated with emapalumab.
The activation of the IFNγ pathway has a well-docu- mented double role both in controlling mycobacterial infections and, also, in sustaining HLH hyperinflammato- ry response.10,11 In our patient, we had to face both chal- lenges: on the one hand to prevent TB reactivation and on the other to inhibit the hyperinflammation responsi- ble for both HLH and GF.
Upon review of emapalumab safety and efficacy data reported in primary2,12,13 and secondary14 HLH, and despite the potential risk of TB reactivation, the benefit/risk ratio of treating with emapalumab was deemed favorable. Interestingly, during emapalumab treatment, the initial TB abscesses remained inactive and brain TB findings improved. In this context, neutraliza- tion of IFNγ might have contributed to control HLH with- out the prolonged use of additional myelosuppressive drugs. Moreover, since a third GF was not observed, our findings suggest that, in association with other lines of immunosuppressive/chemotherapic agents, emapalumab might have played a role in reducing the risk of graft rejection, as already shown in both murine models and humans.3,15,16 In addition, while an intrinsic defect of the mesenchymal/osteblast compartment in ADA-SCID patients with reduced capacity to support in vitro and in vivo hematopoiesis9 may have contributed to the repeated GF, the concomitant use of Cs-A in the peri-transplant phase and the mega-dose of CD34+ cells infused after the third haplo-HSCT may have played a role in preventing rejection.
This seminal case suggests the feasibility and safety of emapalumab administration to manage secondary HLH and repeated GF also in patients bearing multiple active infections, including TB.
Francesca Tucci,1,2* Vera Gallo,1,2* Federica Barzaghi,1,2 Francesca Ferrua,1,2 Maddalena Migliavacca,1,2
Valeria Calbi,1,2 Matteo Doglio,1 Elena Sophia Fratini,1,3 Zeynep Karakas,4 Sukru Guner,5 Matilde Zambelli,6
Cristina Parisi,6 Raffaella Milani,6 Salvatore Gattillo,6 Benedetta Mazzi,7 Chiara Oltolini,8 Maurizio Barbera,9 Cristina Baldoli,9 Daniela Maria Cirillo,10 Veronica Asnaghi,11 Cristina de Min,11 Maria Pia Cicalese,1,2 Fabio Ciceri,3,12 Alessandro Aiuti1,2,3 and Maria Ester Bernardo1,2
1Pediatric Immunohematology Unit and BMT Program, IRCCS San Raffaele Scientific Institute, Milan, Italy; 2San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy; 3Vita-Salute San Raffaele University, Milan, Italy; 4Department of Pediatrics, Division of Hematology and Oncology, Istanbul University, Faculty of Medicine, Istanbul, Turkey; 5Department of Pediatrics, Division of Immunology and Allergy, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey; 6Immunohematology and Transfusion Medicine Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; 7Immunogenetics, HLA and Chimerism Laboratory, IRCCS San Raffaele Scientific Institute, Milan,
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