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Case Reports
the context of HLA-haploidentical HSCT treated with emapalumab in the presence of concomitant life-threat- ening infections including disseminated bacille Calmette- Guérin disease (BCGitis).
The patient is a 4-year old girl with severe combined immunodeficiency caused by adenosine deaminase defi- ciency (ADA-SCID) referred to our institution for ex vivo hematopoietic stem cell (HSC)-gene therapy (GT) with Strimvelis® in the absence of a human leukocyte antigen (HLA)-identical sibling donor.6 She was in poor clinical condition at presentation with bilateral abscesses on lower limbs, corresponding to the sites of polyethylene glycol-modified adenosine deaminase (PEG-ADA) injec- tions (Figure 1A). Presence of Mycobacterium bovis was identified by direct next-generation sequencing per- formed on the material drained from the limb abscesses using the Deeplex® Myc-TB, an all-in-one test for species- level identification, genotyping and prediction of antibi- otic resistance in Mycobacterium tuberculosis complex. Results were further confirmed by standard mycobacteri- ology procedure and whole genome sequencing of the strain. Moreover, magnetic resonance imaging (MRI) documented an intracerebral granuloma (Figure 1C) and vertebral osteolytic lesions, that, along with the limb abscesses, led to the diagnosis of disseminated BCGitis, as reactivation of the BCG vaccine strain received at birth. She was treated with surgical incision of the abscesses and anti-TB treatment (four-drug regimen [iso- niazid, rifampicin, ethambutol, moxifloxacin] for 12 months as intensive phase; two-drug regimen [isoniazid, rifampicin] for 6 months as continuation phase). After 7 months of anti-TB treatment, at resolution of cutaneous abscesses and with residual encephalic mycobacterial lesions, the patient was considered eligible and treated with Strimvelis®. Failure of engraftment of gene-correct- ed HSC was declared at day +90 and enzyme replace- ment therapy (ERT) was resumed.
Subsequently, due to the lack of a matched unrelated donor and after ERT withdrawal, the patient received a first HLA-haploidentical HSCT after αβ+ T-cell and CD19+ B-cell depletion (TCD) from the father after reduced toxicity conditioning regimen (Table 1).7 However, HSCT failed due to primary GF, likely related to concomitant adenovirus reactivation in the peri- engraftment phase. A second paternal haplo-HSCT was performed after reduced intensity conditioning employ- ing exceeding HSC cryopreserved from the first trans- plant and infused on d+31 post first HSCT (Table 1).
On day +13 after the second haplo-HSCT, the patient showed persistent fever, hepatosplenomegaly, high levels of triglycerides (383 mg/dL) and markedly elevated inflammatory markers such as ferritin (18,000 mg/dL) and soluble IL2 receptor (16,809 pg/mL; reference values 600-2,000) (Figure 2A and B). Donor chimerism on both peripheral blood (PB) and bone marrow (BM) was docu- mented on days +10 and +13, respectively; however, it was followed by secondary GF with complete loss of donor engraftment (day +18). BM morphology showed hypocellularity with features of active hemophagocyto- sis. A secondary HLH was diagnosed based on 6 out of 8 HLH-2004 criteria,8 likely triggered by concurrent infec- tions, including Stenotrophomonas maltophilia bacteremia, invasive pulmonary aspergillosis (Figure 1E) and aden- ovirus reactivation. Treatment with methylprednisolone (2 mg/kg/day) and high-dose immunoglobulins was start- ed.
In order to control HLH and reduce the possibility of GF after a third HSCT, compassionate use of emapalum- ab was requested and approved for this severely
immunocompromised patient unable to tolerate standard HLH immunochemotherapy.
At time of emapalumab initiation, adenovirus reactiva- tion and invasive pulmonary aspergillosis were active: adenovirus was detected both in plasma and stool with 1,940 copies/mL and >1,000,000 copies/mL, respectively; while galactomannan levels were above the upper limit of detection (index >6). Intensive antimicrobial treatment included antivirals (intravenous cidofovir, later switched to oral brincidofovir) and antifungals (voriconazole plus anidulafungin, later switched to liposomial ampho- tericine-B plus anidulafungin to minimize drugs interac- tions). Conversely, rifampicin and isoniazid were contin- ued as secondary prophylaxis to avoid the risk of reacti- vation of TB, which was regularly monitored through blood cultures, fecal polymerase chain reaction (PCR) for Mycobacterium bovis and brain MRI. Emapalumab was administered intravenously twice a week for a total of 15 infusions with the objective of prompt tapering of gluco- corticoids. After the first dose at 1 mg/kg, emapalumab dose was increased to 3 mg/kg: the laboratory parame- ters, while not worsening, did not show any satisfactory improvement. Thereafter, emapalumab dose was increased to 6 mg/kg, based on deterioration of inflam- matory parameters (e.g., ferritin, C-reactive protein) (Figure 2A). IFNγ levels were not particularly elevated in this patient, as documented by CXCL9 values around 260 pg/mL at start of emapalumab treatment (Figure 2B). Nonetheless, the pharmacokinetics (PK) of emapalumab (Figure 2C) was affected by target-mediated drug disposi- tion, documenting high IFNγ production and requiring emapalumab dose increase. CXCL9 progressively decreased to levels below 80 pg/mL, documenting com- plete neutralization of IFNγ. By the time of the third haplo-HSCT, glucocorticoids dose was reduced to approximately 50% of the starting dose, while maintain- ing a good clinical control of HLH. The patient, despite the occasional temporary worsening of a few HLH labo- ratory parameters, did not progress into overt HLH, likely due to the neutralization of IFNγ.
The patient received the third TCD haplo-HSCT from the mother after a total of six emapalumab doses. Conditioning regimen included chemotherapeutic agents active against HLH,8 while cyclosporine-A (Cs-A) was added for graft-rejection prevention (Table 1). Anti-HLA antibodies were undetectable before and after HSCT. Neutrophil and platelet engraftment occurred on days +10 and +14, respectively. BM aspirate at day +21 was normo-cellulated with no evidence of hemophagocytosis and showed full donor chimerism. Emapalumab was administered until achievement of sustained donor engraftment (day +28) (Figure 1G). No adverse events occurred. HLH clinical and laboratory parameters pro- gressively improved (Figure 2A and B) allowing Cs-A and steroids tapering and ultimately discontinuation (days +36 and +59, respectively) (Figure 1G).
Remarkably, during blockade of IFN-γ with emapalum- ab, infections remained stable or improved with antimi- crobial medications. At the end of treatment, no sign of reactivation of cutaneous TB lesions was observed (Figure 1B) and the brain imaging showed improvement of the lesions documented prior to emapalumab (Figure 1D). Bacteremia resolved and invasive pulmonary Aspergillosis improved with favorable radiological evolu- tion (Figure 1F) and reduction of galactomannan up to negativity at day +132 post HSCT. After 8-week treat- ment with emapalumab, at day +39 post HSCT, aden- ovirus became undetectable in plasma. Treatment with brincidofovir was continued until negativity also in stool
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