Description 
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.

Policy
Tagraxofusp-erzs (Elzonris) is considered MEDICALLY NECESSARY for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) when the following criteria is met:

• The patient is > 2 years of age.

• The patient has adequate cardiac function and serum albumin greater than or equal to 3.2g/dL prior to every course of therapy.

• The patient has an ECOG score of 0 – 2.

• The patient does not have a diagnosis of acute promyelocytic leukemia (APL, FAB M3).

• Elzonris is prescribed by or consultation with an oncologist.

• Each individual dose must not exceed 12 mcg/kg administered intravenously.

• Confirmed positive for CD123 expression.

• Patient does not have significant cardiovascular disease (e.g., uncontrolled or any NYHA Class 3 or 4 congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of initiating therapy, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication, baseline left ventricular ejection fraction < 40%).

Continuation of therapy is considered MEDICALLY NECESSARY for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) when the following criteria is met:

• Patient continues to meet the initial criteria

• Absence of unacceptable toxicity from the drug. Examples include any of the following: capillary leak syndrome (i.e., hypoalbuminemia, edema/weight gain, pulmonary edema, hypotension, etc.), severe hypersensitivity, severe hepatotoxicity (e.g.,  AST/ALT > 5 times the upper limit of normal), nephrotoxicity (e.g., serum creatinine > 1.8 mg/dL or creatinine clearance ≤ 60 mL/minute), cardiovascular effects (e.g., systolic blood pressure ≥ 160 mmHg or ≤ 80 mmHg; or heart rate ≥ 130 bpm or ≤ 40 bpm), etc.

• Disease stabilization or improvement as evidenced by a complete response [CR] (i.e., morphologic, cytogenetic or molecular complete response CR) or clinical complete response [CRc] ( i.e., complete response with residual skin abnormality not indicative of active disease)

Tagraxofusp-erzs is considered NOT MEDICALLY NECESSARY for all other indications.

We recognize uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

Rationale
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 Dec. 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).

The labeling for Elzonris contains a boxed warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment. Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (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.

Appendix
Pre-medicate with an H1-histamine antagonist, acetaminophen, corticosteroid and H2-histamine antagonist prior to each Elzonris infusion. Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL before administering Elzonris.

Elzonris is administered intravenously at 12 mcg/kg over 15 minutes once daily on days 1 to 5 of a 21-day cycle. The dosing period may be extended for dose delays up to day 10 of the cycle. Continue treatment until disease progression or unacceptable toxicity.

The first cycle of Elzonris is administered in the inpatient setting with patient observation through at least 24 hours after the last infusion. Subsequent cycles may be administered in the inpatient or appropriate outpatient setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for a minimum of 4 hours following each infusion.

Refer to the full prescribing information for additional information for dose modifications.

References 

1. U.S. Food and Drug Administration (FDA). Elzonris (tagraxofusp-erzs) injection, for intravenous use. Prescribing Information. Reference ID: 4367191. Rockville, MD: FDA; revised December 2018.

2. Gurbuxani S. Blastic plasmacytoid dendritic cell neoplasm. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2018.

3. Sullivan JM, Rizzieri DA. Treatment of blastic plasmacytoid dendritic cell neoplasm. Hematology Am Soc Hematol Educ Program. 2016;2016(1):16-23.

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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