Tagraxofusp-erzs (Elzonris)

Number: 0947

Policy

1. Criteria for Initial Approval
   
   Aetna considers tagraxofusp-erzs (Elzonris) medically necessary for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) when the member’s disease is positive for CD123 expression.
   
   
Aetna considers all other indications as experimental and investigational.
2. Continuation of Therapy
   
   Aetna considers continuation of tagraxofusp-erzs (Elzonris) therapy medically necessary for members with an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Elzonris (tagraxofusp-erzs) is available for injection as 1,000 mcg in 1 mL signle-dose vial for intravenous use. 

Blastic plasmacytoid dendritic cell neoplasm (BPDCN): Premedicate with an H1-histamine antagonist, acetaminophen, corticosteroid and H2-histamine antagonist prior to each infusion. Administer Elzonris intravenously at 12 mcg/kg over 15 minutes once daily on days 1 to 5 of a 21-day cycle. Administer the first cycle of Elzonris in the inpatient setting. Subsequent cycles may be administered in the inpatient or appropriate outpatient setting.

Source: Stemline Therapeutics, Inc., 2018.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Elzonris is a CD123-directed cytotoxin for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older.

Tagraxofusp-erzs is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that inhibits protein synthesis and causes cell death in CD123-expressing cells (Stemline Therapeutics, 2018).

Elzonris (tagraxofusp-erzs) carries a black box warning for capillary leak syndrome (CLS), which can be life-threatening and fatal. In patients receiving tagraxofusp-erzs in clinical trials, the overall incidence of CLS was 55% (52/94), including Grade 1 or 2 in 46% (43/94), Grade 3 in 6% (6/94), Grade 4 in 1% (1/94) and 2 fatal events (2/94, 2%). Common signs and symptoms (incidence ≥ 20%) associated with CLS that were reported during treatment include hypoalbuminemia, edema, weight gain, and hypotension. Other warnings and precautions include hypersensitivity and hepatoxicity. The most common adverse reactions (incidence ≥ 30%) are capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia and weight increase. Most common laboratory abnormalities (incidence ≥ 50%) are decreases in albumin, platelets, hemoglobin,calcium, and sodium, and increases in glucose, ALT and AST. Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby (Stemline Therapeutics, 2018).

Blastic Plasmacytoid Dendritis Cell Neoplasm (BPDCN)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and rare hematologic neoplasm that can affect multiple organs, including the lymph nodes and the skin. The exact incidence of BPDCN is unknown, but the disease is more common in men than women and in patients 60 years and older. There are no known environmental or hereditary genetic factors predisposing to the development of BPDCN. BPDCN can occur as an isolated disease or in the context of other hematologic neoplasms (e.g., myelodysplastic syndrome, chronic myeloid leukemia, chronic myelomonocytic leukemia, and acute myeloid leukemia); however, the relationship between BPDCN and other myeloid malignancies is not clearly understood.

The nomenclature used to describe BPDCN has changed over the years with increased understanding of the underlying biology. In 1995, the tumor was initially described as an acute agranular CD4-positive natural killer (NK) cell leukemia. In the following years, the name changed to "blastic NK cell lymphoma", and then "agranular CD4+CD56+ hematodermic neoplasm/tumor". The current term, blastic plasmacytoid dendritic cell neoplasm (BPDCN), was used by the 2008 World Health Organization classification of tumors of the hematopoietic and lymphoid tissues when it was understood that the tumor is derived from plasmacytoid dendritic cells (type 2 dendritic cells). To date, the standard of care has been intensive chemotherapy followed by bone marrow transplantation. 

In their review, Sullivan et al (2016) state blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy with no defined standard of care. BPDCN presents most commonly with skin lesions with or without extramedullary organ involvement before leukemic dissemination. As a result of its clinical ambiguity, differentiating BPDCN from benign skin lesions or those of acute myeloid leukemia with leukemia cutis is challenging. BPDCN is most easily defined by the phenotype CD4+CD56+CD123+lineage-MPO-, although many patients will present with variable expression of CD4, CD56, or alternate plasmacytoid markers, which compounds the difficulty in differentiating BPDCN from other myeloid or lymphoid malignancies. Chromosomal aberrations are frequent, and the mutational landscape of BPDCN is being rapidly characterized although no obvious molecular target for chemoimmunotherapy has been identified. Chemotherapy regimens developed for acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndrome have all been used to treat BPDCN. Relapse is frequent, and overall survival is quite poor. Allogeneic transplantation offers a chance at prolonged remission and possible cure for those who are eligible; unfortunately, relapse remains high ranging from 30% to 40%. Novel therapies such as SL-401, a diphtheria toxin conjugated to interleukin-3 (IL-3) is commonly overexpressed in BPDCN and other aggressive myeloid malignancies and has shown considerable promise in ongoing clinical trials. Future work with SL-401 will define its place in treating relapsed or refractory disease as well as its role as a first-line therapy or bridge to transplantation.

On December 21, 2018, the U.S. Food and Drug Administration (FDA) approved Elzonris (tagraxofusp-erzs; SL-401) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older. Elzonris (tagraxofusp-erzs) is a CD123-directed cytotoxin, is a fusion protein comprised of a recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT). Tagraxofusp-erzs is constructed by recombinant DNA technology and produced in Escherichia coli cells. The efficacy of Elzonris was studied in two cohorts of patients in a multicenter, open-label, single-arm clinical trial (STML-401-0114; NCT 02113982; Study 0114). The first trial cohort enrolled 13 patients with treatment-naive BPDCN. Treatment consisted of Elzonris 12 mcg/kg intravenously over 15 minutes once daily on days 1 to 5 of a 21-day cycle. Efficacy was based on the rate of complete response (CR) or clinical complete response (CRc). CRc is defined as complete response with residual skin abnormality not indicative of active disease. The median time to CR/CRc was 57 days (range: 14 to 107). Seven patients (54%; 95% CI: 25.1, 80.8.) achieved complete remission (CR) or (CRc). The median duration of CR/CRc in months was not reached (range: 3.9 to 12.2 months). The median duration of follow up was 11.5 months (range: 0.2 to 12.7 months).

The second cohort included 15 patients with relapsed or refractory BPDCN. Treatment consisted of Elzonris 12 mcg/kg on days 1 to 5 of each 21-day cycle. In this cohort, one patient achieved a CR (duration: 111 days) and one patient achieved a CRc (duration: 424 days).

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9269	Injection, tagraxofusp-erzs, 10 mcg
ICD-10 codes covered if selection criteria are met:
C86.4	Blastic NK-cell lymphoma

The above policy is based on the following references: