Coverage Policy Manual
Policy #: 2020012
Category: Pharmacy
Initiated: June 2020
Last Review: June 2022
  Tagraxofusp-erzs (e.g., Elzonris)

Description:
Tagraxofusp-erzs, a CD 123-directed cytotoxin, is a fusion protein comprised of a recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT). It inhibits protein synthesis and causes cell death in CD123-expressing cells. Tagraxofusp-erzs is constructed by recombinant DNA technology and produced in Escherichia coli cells.  
 
Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress IL-3 receptor subunit alpha or CD123. It is more common in adults (median age, 65-67 yrs) with an approximate male to female ratio of 3:1. Tagraxofusp-erzs has shown potent antitumor activity against BPDCN cells with cytotoxicity at femtomolar concentrations
 
Regulatory Status
 
On December 21, 2018 the FDA approved tagraxofusp-erzs (e.g., Elzonris®) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients 2 yrs and older.
 
Tagraxofusp-erzs (e.g., Elzonris®) contains a black box warning for capillary leak syndrome (CLS). In clinical trials, the overall incidence of CLS was 55%, including Grade 1 or 2 in 46%, Grade 3 in 6%, Grade 4 in 1% and 2 fatal events. Common signs and symptoms (incidence ≥ 20%) associated with CLS that were reported during treatment with Tagraxofusp-erzs (e.g., Elzonris®) include hypoalbuminemia, edema, weight gain, and hypotension.  
 
Coding
 
J9269     Injection, targraxofusp erzs, 10 micrograms
 

Policy/
Coverage:
Effective June 1,2020, Prior Approval is required for Tagraxofusp-erzs (e.g., Elzonris®)
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.  
 
Effective January 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients 2 years and older meets primary coverage criteria when ALL the following criteria are met:
 
        • Must be > *2 years old.  (FDA, Elzonris 2018)
        • Must have documentation of diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) (FDA, Elzonris 2018)
        • Have an albumin level of > 3.2 g/dL (FDA, Elzonris 2018)
        • Must ordered by a physician with expertise in diagnosing and treating BPDCN   
 
* Would encourage participation in a clinical trial for ages 2-15.
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
    • Administer tagraxofusp-erzs 12 mcg/kg IV over 15 mins once daily on days 1 to 5 of a 21-day cycle. Continue treatment with tagraxofusp-erzs until disease progression of unacceptable toxicity.
    • Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL.
    • The first cycle should be administered in an inpatient setting with patient observation through at least 24 hours.
    • Subsequent cycles may be administered in the inpatient or in a suitable outpatient ambulatory care 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.  
    • Monitor vital signs, albumin, transaminases, and creatinine prior to preparing each dose.  Please see FDA prescription guidance for recommended dose modifications and CLS management guidelines.  
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
For members with contracts without primary coverage criteria, the use of tagraxofusp-erzs in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective November 2021 through December 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use tagraxofusp-erzs (Elzonris®) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients 2 yrs and older meets primary coverage criteria when ALL the following are met
 
        • Must be > *2 yrs old.  
        • Must have an ECOG of < 2
        • Must have documentation of diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN)
        • Have an albumin level of > 3.2 g/dL
        • Must ordered by a physician with expertise in diagnosing and treating BPDCN
 
* Would encourage participation in a clinical trial for ages 2-15.
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
        • 0 = Fully active, able to carry on all pre-disease performance without restriction
        • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
        • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
        • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
        • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
        • 5 = Dead
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
    • Administer tagraxofusp-erzs (Elzonris®) 12 mcg/kg IV over 15 mins once daily on days 1 to 5 of a 21-day cycle. Continue treatment with tagraxofusp-erzs until disease progression of unacceptable toxicity.
    • Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL.
    • The first cycle should be administered in an inpatient setting with patient observation through at least 24 hours.
    • Subsequent cycles may be administered in the inpatient or in a suitable outpatient ambulatory care 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.  
    • Monitor vital signs, albumin, transaminases, and creatinine prior to preparing each dose.  Please see FDA prescription guidance for recommended dose modifications and CLS management guidelines.  
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
For members with contracts without primary coverage criteria, the use of tagraxofusp-erzs (Elzonris®) in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
 
Effective June 2021 through October 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use tagraxofusp-erzs (Elzonris®) for blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients 2 yrs and older meets primary coverage criteria when ALL the following are met
 
          • Must be > *2 yrs old.  
          • Must have an ECOG of < 2
          • Must have documentation of diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN)
          • Have an albumin level of > 3.2 g/dL
          • Must ordered by a physician with expertise in diagnosing and treating BPDCN
 
* Would encourage participation in a clinical trial for ages 2-15.
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
        • 0 = Fully active, able to carry on all pre-disease performance without restriction
        • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
        • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
        • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
        • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
        • 5 = Dead
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1, 2A, and 2B recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
    • Administer tagraxofusp-erzs (Elzonris®) 12 mcg/kg IV over 15 mins once daily on days 1 to 5 of a 21-day cycle. Continue treatment with tagraxofusp-erzs until disease progression of unacceptable toxicity.
    • Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL.
    • The first cycle should be administered in an inpatient setting with patient observation through at least 24 hours.
    • Subsequent cycles may be administered in the inpatient or in a suitable outpatient ambulatory care 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.  
    • Monitor vital signs, albumin, transaminases, and creatinine prior to preparing each dose.  Please see FDA prescription guidance for recommended dose modifications and CLS management guidelines.  
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
For members with contracts without primary coverage criteria, the use of tagraxofusp-erzs (Elzonris®) in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.

Rationale:
Pemmaraju N, Lane A and Sweet K (2019) performed a Phase I/II multicenter, multi-cohort, open-label, single-arm study (NCT 02113982).  Forty-seven patients with BPDCN were enrolled, including 32 treatment-naïve and 15 previously treated patients. Patients received tagraxofusp-erzs intravenously on days 1-5 of a 21-day cycle for multiple consecutive cycles. Efficacy was based on the rate of complete response of clinical complete response (CR/CRc), with CRc defined as complete response with residual skin abnormality not indicative of active disease.  
 
Outcomes from the study included 29 previously untreated patients with BPDCN who had a 90% overall response rate (ORR) and 72% complete response rate (CR).  In 13 patients with relapsed or refractory BPDCN, ORR and CR were 69% and 38%, respectively The CR/CRc rate was 53.8% (7/13) (95% CI:25.1, 80.8).  The median duration of CR/CRc was not reached (range:3.9 – 12.2 months).  The median overall survival (OS), among 29 treatment–naïve patients who received tagraxofusp-erzs was not reached (range:0.2 – 42 month, with median follow-up of 23.0 months [range: 0.2 – 41 months]).
 
Specifically, 7 (53.8%, 95% CI: 25.1, 80.8) of 13 patients with untreated BPDCN achieved CR/CRc after a median follow-up of 11.5 months.  The median response duration was not reached.  In the second cohort of 15 patients with relapsed or refractory BPDCN, 1 patient achieved a CR (duration 424 days).  After therapy, 45% of patients (13 of 29) were bridged to stem cell transplant.  
 
Capillary leak syndrome (CLS), including life-threatening and fatal cases, has been reported among patients treated with tagraxofusp-ezrs. In the 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% (2/94). Hence the black box warning.
 
The FDA based approval for ages >2 yrs to 17 on a study by Armin G. Jegalian et al (2010) as well as studies with unpublished results at this time. The 2010 study was a retrospective study that reviewed 29 pediatric patients with blastic plasmacytoid dendritic cell neoplasm.  Analysis showed that the overall survival rate (OS) was 72%, 25 patients with follow-up and all had received chemotherapy, (follow-up ranging from 9 months to 13 yrs with a median of 30 months).  The event-free survival rate was 64%.   Nine patients were alive 5 years after original diagnosis and 3 of the 5 had undergone hematopoietic stem cell transplantation-one in first complete remission and two in second remission. 7 patients who lacked cutaneous disease at presentation had a 100% survival rate.  Of those seven, five were still alive more than 5 years after diagnosis, and 2 had undergone stem cell transplantation.  Among 18 patients that presented with cutaneous disease, only 11 survived (61%).
 
In conclusion, BPDCN in children is clinically less aggressive than in adults where long term survival may depend on SCT.  Treatment with high-risk acute lymphoblastic leukemia-type chemotherapy appears to be effective and SCT may be reserved for children who relapse and achieve a second remission.  Outcomes were more favorable in cases that lacked cutaneous disease at presentation.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
J9269Injection, tagraxofusp erzs, 10 micrograms

References: Elzonris® (tagraxofusp-ezrs) [package insert). New York, NY Stemline Therapeutics Inc.

Jegalian AG, Buxbaum NP, Facchetti F, et al.(2010) Blastic plasmacytoid dendritic cell neoplasm in children: diagnostic features and clinical implications. Haematologica. 2010 Nov;95(11):1873-9. Epub 2010 Jul 27.

Pemmaraju N, Lane AA, Sweet KL et al.(2019) Tagraxofusp in Balstic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med 2019 Apr 25;380(17):1628-1637.doi: 10.1056/NEJMoa1815105.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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