wor absent NK-cell activity, ferritin ≥ 500 mcg/L, soluble CD25 ≥ 2400 U/mL. Patients had to
have evidence of active disease as assessed by treating physician.
Patients had to fulfill one ofthe following criteria as assessed by the treating physician: having not responded or not achieveda satisfactory response or not maintained a satisfactory response to conventional HLH therapy, orintolerance to conventional HLH treatments.
Patients with active infections caused by specific
pathogens favored by IFNγ neutralization were excluded from the trial (e.g., mycobacteria andHistoplasma Capsulatum). Patients received prophylaxis for Herpes Zoster, Pneumocystisjirovecii, and fungal infections.
Twenty-seven patients enrolled and received treatment in the study and twenty patients (74%)completed the study. Seven patients (26%) were prematurely withdrawn. Twenty-two patients(81%) enrolled onto the open-label extension study which monitored patients for up to 1 yearafter HSCT or after the last GAMIFANT infusion (NI-0501-05; NCT02069899).
The study treatment duration was up to 8 weeks after which patients could continue treatment onthe extension study. All patients received an initial starting dose of GAMIFANT of 1 mg/kgevery 3 days. Subsequent doses could be increased to a maximum of 10 mg/kg based on clinicaland laboratory parameters interpreted as unsatisfactory response.
Forty-four percent of patientsremained at a dose of 1 mg/kg, 30% of patients increased to 3-4 mg/kg and 26% of patientsincreased to 6-10 mg/kg. The median time to dose increase was 27 days (range: 3-31 days) with22% of patients requiring a dose increase in the first week of treatment.
All patients received dexamethasone as background HLH treatment with doses between 5 to 10mg/m2/day. Cyclosporine A was continued if administered prior to screening. Patients receivingmethotrexate and glucocorticoids administered intrathecally at baseline could continue thesetreatments.
In Study NI-0501-04, the median patient age was 1 year (0.2 to 13). Fifty-nine percent of thepatients were female, 63% were Caucasian, 11% were Asian, and 11% were Black.
A genetic mutation known to cause HLH was present in 82% of patients. The most frequentcausative mutations were FHL3-UNC13D (MUNC 13-4) (26%), FHL2-PRF1 (19%), and
Griscelli Syndrome type 2 (19%).
The HLH mutations in the population enrolled are described in Table 3.
Table 3: HLH Mutations in Patients with Primary HLH with Prior Therapy
GAMIFANT
(N=27)
HLH Genetic Confirmation 22 (82)
FHL3 – UNC13D 7 (26)
FHL2 – PRF1 5 (19)
Griscelli Syndrome type 2 (RAB27A) 5 (19)
FHL5 – STXBP2 (UNC18B) 2 (7.4)
FHL4 – STX11 1 (3.7)
X-linked Lymphoproliferative Disorder
1
1 (3.7)
X-linked Lymphoproliferative Disorder
2
1 (3.7)
All patients received previous HLH treatments. Patients received a median of 3 prior agentsbefore enrollment into the trial. Prior regimens included combinations of the following agents:
dexamethasone, etoposide, cyclosporine A, and anti-thymocyte globulin.
At baseline entry into the study, 78% of patients had elevated ferritin levels, thrombocytopenia(70% with platelet count of < 100 x 109
cells/L), hypertriglyceridemia (67%) with triglyceridelevel > 3 mmol/L. Central nervous system findings were present in 37% of patients.
Forty-onepercent of patients had active infections not due to specific pa |
