Elzonris Adverse Reactions

Summary of the safety profile: The most serious adverse reaction that may occur during ELZONRIS treatment is CLS (see Dosage & Administration and Precautions) which was reported in 18% of patients with a median time to onset of CLS of 6 days.
Adverse reactions occurring in ≥ 20% of patients treated with ELZONRIS were hypoalbuminemia, increased transaminases, thrombocytopenia, nausea, fatigue and pyrexia.
Adverse reactions grade 3 and above according to the Common Terminology Criteria for Adverse events (CTCAE) and occurring in > 5% of patients were increased transaminases, thrombocytopenia and anaemia.
Tabulated list of adverse reactions: The adverse reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100).
The adverse reactions described in this section were identified in clinical studies of patients with haematologic malignancies (N=176), including 89 patients with BPDCN. In these studies, ELZONRIS was administered as monotherapy at doses of 7 mcg/kg (12/176, 7%), 9 mcg/kg (9/176, 5%) and 12 mcg/kg (155/176, 88%). Incidence and severity of adverse reaction in patients with BPDCN were similar to those of the entire studied population. (See Table 5.)

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Description of selected adverse reactions: Capillary leak syndrome: Capillary leak syndrome was reported in 18% (32/176), with 12% (21/176) Grade 2, 3% (6/176) Grade 3, 1% (2/176) Grade 4, and fatal in 1.7% (3/176). Of the 25 patients that resumed treatment after experiencing an event of CLS, only 1 patient experienced a recurrence of CLS. The median time to onset of CLS was short (6 days), with all but 2 patients experiencing the first onset of CLS in cycle 1. No patient experienced the first onset of CLS after cycle 2. The overall incidence of CLS was similar in patients with BPDCN (20%, 18/89), including 12% (11/89) Grade 2, 2% Grade 3 (2/89), 2% Grade 4 (2/89) and 3 fatal cases (3%). Patients are required to have adequate cardiac function prior to administration of ELZONRIS (see Dosage & Administration and Precautions).
Hepatotoxicity: ALT and AST elevations were reported as adverse reactions in 47% (83/176) and 46% (81/176) of patients treated with ELZONRIS monotherapy, respectively. ≥ Grade 3 ALT and AST increased were reported in 23% (40/176) and 23% (40/176), respectively. Elevated liver enzymes occurred in the majority of patients in cycle 1 and were reversible following dose interruptions (see Precautions). Similar onset time and incidence were observed in patients with BPDCN, with 51% (45/89) of patients experiencing adverse events of ALT and AST elevations, with ≥ Grade 3 ALT and AST increased reported in 28% (25/89) and 29% (26/89) respectively. Two patients with BPDCN met the laboratory criteria for Hy's Law; in both cases the laboratory abnormalities were noted during Cycle 1.
Haematological abnormalities: Thrombocytopenia was reported in 30% (53/176) of patients treated with ELZONRIS monotherapy and in 35% (31/89) of patients with BPDCN. Thrombocytopenia Grade ≥ 3 was reported in 23% (40/176) of patients treated with ELZONRIS monotherapy and in 26% (23/89) of patients with BPDCN. The majority of thrombocytopenia events were reported in cycle 1 and cycle 2 of treatment. Neutropenia was reported in 9% (15/176) of patients treated with ELZONRIS monotherapy and in 11% (10/89) of patients with BPDCN, with events ≥ Grade 3-reported in 6% (11/176) and 8% (7/89), respectively.
Hypersensitivity: Reactions representative of hypersensitivity were reported in 19% (33/176) of patients treated with ELZONRIS monotherapy and in 17% (15/89) of patients with BPDCN, with events ≥ Grade 3 reported in 3% (6/176) and 4% (4/89), respectively (see Precautions).
Immunogenicity: Immune response was evaluated by assessment of serum binding reactivity against tagraxofusp (anti-drug antibodies; ADA) and neutralising antibodies by inhibition of functional activity. Immune response was assessed using two immunoassays. The first assay detected reactivity directed against tagraxofusp (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of tagraxofusp. Two cell-based assays were used to investigate the presence of neutralising antibodies by inhibition of a cell-based functional activity.
In 190 patients treated with ELZONRIS in four clinical studies: 94% (176/187) of patients evaluable for the presence of pre-existing ADA at baseline before treatment were confirmed positive with 27% being positive for the presence of neutralising antibodies. The high prevalence of ADA at baseline was anticipated due to diphtheria immunisation.
100% (N=170) of patients evaluable for treatment-emergent ADA tested positive with most patients showing an increase in ADA titre by the end of Cycle 2 of ELZONRIS.
92% (155/169) of ADA-positive patients evaluable for the presence of neutralising antibodies post-treatment were neutralising antibody-positive.
75% (129/171) of patients evaluable for treatment-emergent anti-IL-3 antibodies tested positive with most patients testing positive by Cycle 3 of ELZONRIS.
74% (93/126) of patients who tested positive for anti-IL-3 antibodies and were evaluable for the presence of neutralising antibodies were neutralising antibody-positive.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions according to the guideline issued by local authority.