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CASE REPORTS
Emapalumab treatment in an ADA-SCID patient with refractory hemophagocytic lymphohistiocyto- sis-related graft failure and disseminated bacillus Calmette-Guérin infection
Interferon gamma (IFNγ)-targeted immunotherapy with emapalumab, a fully human monoclonal antibody, was recently approved by the US Food and Drug Administration for the treatment of adult and pediatric patients with primary hemophagocytic lymphohistiocy- tosis (HLH) who have refractory, recurrent or progressive disease or intolerance with conventional HLH therapy.1,2 Moreover, emapalumab has shown promising efficacy in the treatment of patients with graft failure (GF) requiring a second allogeneic hematopoietic stem cell transplanta- tion (HSCT).3 Interestingly, there is growing evidence to
support common pathophysiolological mechanisms between HLH and immune-mediated GF, highlighting the key role of IFNγ in both conditions.3
IFNγ is a cytokine produced by macrophages and lym- phocytes that plays a critical role in both innate and adaptive immune responses. In patients with complete IFNγ receptor deficiency or developing anti-IFNγ auto- antibodies, the absence of IFNγ biological activity leads to an increased susceptibility to specific infections, such as mycobacterial infections.4,5 For this reason, latent tuber- colosis (TB) infection represented an exclusion criterion in clinical trials investigating the therapeutic role of ema- palumab in primary (clinicaltrials.gov identifiers: NCT03312751; NCT01818492) and secondary (clinicaltri- als.gov identifiers: NCT03311854) HLH.
Here we report a case of secondary HLH-related GF in
Table 1. Characteristics of the three HLA-haploidentical (haplo)-hematopoietic stem cell transplantations performed. I II III
Donor
Conditioningregimen
GvHD prophylaxis
Cell dose
CD34+ cells, x106kg
TCR-αβ+
CD3+x104/kg
TCR-γd+ CD3+, ×106/kg CD20+ ×104/kg
CD3-CD19-CD20-, ×106/kg
Engraftment's kinetic
Neutrophils*
Platelets** PB chimerism#
BM chimerism
Father
Treosulfan14g/m2(days-6,-5,-4)
Fludarabine 40 mg/m2 (days -6, -5, -4, -3) ATG grafalon 4 mg/kg (days -5, -4, -3) Rituximab200mg/m2(day-1)
TCD 9.52
9 13.1
12 37
NA NA -
Donor 0%
(day +20)
Father
Fludarabine30mg/m2(days-5;-4,-3)
Cyclophosphamide 500 mg/m2
(days -5, -4, -3) ATGthymoglobulin2mg/kg(days-3,-2) Rituximab200mg/m2 (day-1)
TCD 10.5
10 14.6
13 41
NA
NA
Donor >90% (day +10)§
Donor >70% (day +13)§
Host >90% (day +18)§
Donor 0%; host >99% (day +28)
Donor >70%; host 2.3% (day +13)
Donor 0%; host >99% (day +20)
Mother
VP-16150mg/m2 (days-5,-4,-3)
Cyclophosphamide 500 mg/m2 (days -5,-4,-3) ATGgrafalon2mg/kg(days-3,-2) Cyclosporine-A3mg/kg
(from day -2 to +36) TCD
- αβ+CD19+-depleted CD34+=8.09; - positively selected CD34+=15.01 Total CD34+ =23.1
9
6.7
9 13
+10 days
+14 days
2nd donor 86%; host 1.2%; 1st
donor absent (father) (day +12)
2nd donor 89%; host 0.4%;
1st donor absent (father) (day +18) 2nd donor >95%; host 0%;
1st donor absent (father) (day +100) 2nd donor >99%; host 0.7%;
1st donor absent (father) (day +21) 2nd donor >90%; host 0%; (day +100)
Haploidentical donors were mobilized with granulocyte-colony stimulating factor (G-CSF) (father) and G-CSF + Plerixafor (mother).*Defined as the time needed to reach an absolute neutrophil count (ANC) >0.5x109/L.**Defined as the time needed to reach an unsupported platelet count >20x109L.Primary graft failure was defined as:ANC <0.5x109/L by day +28, hemoglobin <80 g/L and platelets <20x109/L. Cord blood transplantation: up to day +42. Secondary graft failure was defined as: ANC <0.5x109/L after initial engraftment not related to relapse, infection, or drug toxicity. #Chimerism was assessed on total and/or sorted PB and BM aspirate samples by real-time polymerase chain reaction and relative quantification. At day +100 after the third haplo-HSCT, chimerism analysis was performed also on PB lymphoid and myeloid subpopulations including CD3+ (>90%),CD15+ (>90%) and CD14+ (>85%) cells.§Presence of host/donor cells not evaluated due to insufficient material.HSCT:hematopoietic stem cell trans- plantation;ATG:anti-thymocyte globulin;VP-16:etoposide;GvHD:graft-versus-host disease;TCD:T-cell depletion;TCR:T-cell receptor;NA:not achieved;PB:peripheral blood; BM: bone marrow.
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