Adoptive Immunotherapy

Section: Therapy
Effective Date: April 19, 2019
Revised Date: May 19, 2020
Last Reviewed: May 19, 2020

Retiring Effective: June 1, 2020

Description

The spontaneous regression of certain cancers (e.g., renal cell carcinoma, melanoma) supports the idea that an individual's immune system can delay tumor progression and, on rare occasions, can eliminate tumors altogether. These observations have led to research into various immunologic therapies designed to stimulate a individual's own immune system. Adoptive immunotherapy is a method of activating lymphocytes and/or other types of cells for the treatment of cancer and other diseases. Cells are removed from the individual, processed for some period of time, and then infused back into the individual.

Criteria

Coverage is subject to the specific terms of the member’s benefit plan.

Federal Employee Program members (FEP) should check with their Retail Pharmacy Program to determine if prior approval is required by calling the Retail Pharmacy Program at 1-800-624-5060 (TTY: 1-800-624-5077). FEP members can also obtain the list through the www.fepblue.org website.

Tisagenlecleucel intravenous infusion is considered medically necessary for relapsedaor refractoryb individuals if they meet all of the following criteria:

  • Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblas
  • Are up to 25 years old at the time of infusion
  • Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy
  • Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis
  • Do not have any of the following:
    • Burkitt lymphoma
    • Active hepatitis B, C, or any uncontrolled infection
    • Grade 2 to 4 graft-versus-host disease
    • Concomitant genetic syndrome with the exception of Down syndrome
    • Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion
    • Individual has active central nervous system 3 acute lymphoblastic leukemia (i.e., white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts)

aRelapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant.

bRefractory (resistant) disease is defined as those individuals who fail to obtain complete response with induction therapy, ie, failure to eradicate all detectable leukemia cells (<5% blasts) from the bone marrow and blood with subsequent restoration of normal hematopoiesis (>25% marrow cellularity and normal peripheral blood counts).

Axicabtagene ciloleucel or tisagenlecleucel intravenous (except as indicateda) infusion is considered medically necessary for relapsed or refractoryb individuals if they meet all of the following criteria:

  • Are adults (age ≥18) at the time of infusion
  • Histologically confirmed diagnosis of diffuse large B-cell lymphoma, not otherwise specified; or primary mediastinal large B-cell lymphomaa or high-grade B-cell lymphoma or diffuse large B-cell lymphoma arising from follicular lymphoma
  • Received adequate prior therapy including all of the following
    • Anti-CD20 monoclonal antibody for CD20-positive tumor
    • Anthracycline-containing chemotherapy regimen
    • For subjects with transformed follicular lymphoma, prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to diffuse large B-cell lymphoma
  • Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist

Have not received prior CD19-directed CAR T-cell therapy treatment or any other gene therapy or are being considered for treatment with any other gene therapy

AND

  • Do not have primary central nervous system lymphoma.

a Tisagenlecleucel intravenous infusion is considered investigational for the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma

b Relapsed or refractory disease is defined as progression after 2 or more lines of systemic therapy (which may or may not include therapy supported by autologous cell transplant)

Other applications of adoptive immunotherapy are considered investigational

Policy Guidelines

Autologous lymphocytes used as part of adoptive immunotherapy may be harvested in a pheresis procedure or may be isolated from resected tumor tissue.

The recommended dosage of tisagenlecleucel for individuals with B-cell acute lymphoblastic leukemia who are 50 kg or less is 0.2 to 5.0×106chimeric antigen receptor-positive viable T cells per kilogram of body weight intravenously; for individuals above 50 kg, dose is 0.1 to 2.5×108total chimeric antigen receptor-positive viable T cells (non-weight-based) intravenously.

The recommended target dose of tisagenlecleucel for individuals with large B-cell lymphoma is 0.6 to 6.0 ×108chimeric antigen receptor-positive viable T cells intravenously.

The recommended target dose of axicabtagene ciloleucel for individuals with large B-cell lymphoma is 2×106CAR-positive viable T cells per kg body weight, with a maximum of 2×108chimeric antigen receptor- positive viable T cells intravenously.

Central nervous system (CNS) disease for B-cell acute lymphoblastic leukemia is defined by the following groups:

  • CNS 1: Absence of blasts on cerebrospinal fluid cytospin preparation, regardless of the white blood cell (WBC) count
  • CNS 2: WBC count of less than 5/mL and blasts on cytospin findings
  • CNS 3: WBC count of 5/mL or more and blasts on cytospin findings and/or clinical signs of CNS leukemia (eg, facial nerve palsy, brain/eye involvement, hypothalamic syndrome)

Tisagenlecleucel and axicabtagene ciloleucel have black box warnings because of the risks of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. They should not be administered to individuals with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome be treated with tocilizumab. Individuals should be monitored for neurologic events after treatment.

Tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) are available only through a restricted program under a risk evaluation and mitigation strategy (REMS) called the Kymriah REMS and Yescarta REMS, respectively. The requirement for the REMS components are as follows:

  • Health care facilities that dispense and administer tisagenlecleucel or axicabtagene ciloleucel must be enrolled and comply with the REMS requirements.
  • Certified health care facilities must have onsite, immediate access to tocilizumab, and ensure that a minimum of 2 doses of tocilizumab are available for each individual for administration within 2 hours after tisagenlecleucel or axicabtagene ciloleucel infusion, if needed for treatment of cytokine release syndrome.
  • Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer tisagenlecleucel or axicabtagene ciloleucel are trained to manage cytokine release syndrome and neurologic toxicities.

Procedure Codes

36511 S2107

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Blue Cross Blue Shield of North Dakota may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits.

Diagnosis Codes

B25.9 B97.32 C11.0 C11.1 C11.2 C11.3 C11.8
C11.9 C16.0 C16.1 C16.2 C16.3 C16.4 C16.5
C16.6 C16.8 C16.9 C18.0 C18.1 C18.2 C18.3
C18.4 C18.5 C18.6 C18.7 C18.8 C18.9 C19
C20 C22.0 C22.1 C22.2 C22.3 C22.4 C22.7
C22.8 C22.9 C25.0 C25.1 C25.2 C25.3 C25.4
C25.7 C25.8 C25.9 C34.90 C34.91 C34.92 C43.0
C43.10 C43.111 C43.112 C43.121 C43.122 C43.20 C43.21
C43.22 C43.30 C43.31 C43.39 C43.4 C43.51 C43.52
C43.59 C43.60 C43.61 C43.62 C43.70 C43.71 C43.72
C43.8 C43.9 C64.1 C64.2 C64.9 C65.1 C65.2
C65.9 C71.9 C73

Professional Statements and Societal Positions Guidelines

Practice Guidelines and Position Statements

Current guidelines from the National Comprehensive Cancer Network do not include recommendations for adoptive immunotherapy to treat cancers of the bladder, central nervous system, head and neck, hepatobiliary system, kidney, pancreatic, stomach, or thyroid, melanoma, Hodgkin lymphoma, or non-small-cell lung cancer.

Current National Comprehensive Cancer Network guidelines for acute lymphoblastic leukemia recommend (category 2A) tisagenlecleucel as a treatment option for:

  • Current Network guidelines for B-cell lymphomas recommend (category 2A) axicabtagene ciloleucel or tisagenlecleucel as a treatment option
  • For histological transformation to diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥2 chemo-immunotherapy regimens for the indolent or transformed disease.
  • For relapsed or refractory disease diffuse large B-cell lymphoma after multiple lines of prior therapies which include ≥2 chemo-immunotherapy regimens for the indolent or transformed disease.

     

NCT No.

Trial Name

Planned Enrollment

Completion Date

Cytotoxic-induced killer cells

NCT02118415

Targeted Natural Killer (NK) Cell Based Adoptive Immunotherapy for the Treatment of Individuals With Non-Small Cell Lung Cancer (NSCLC) After Radiochemotherapy (RCT)

90

Feb 2018
(ongoing)

NCT02229266

Randomised Controlled Phase-2 Trial to Determine the Efficacy of Adoptive Immunotherapy With NK Cells in High-risk AML (HINKL)

56

Sep 2020

Tumor-infiltrating lymphocytes

NCT01993719

A Phase II Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Comparing Two Different Chemotherapy Preparative Regimens

64

Sep 2029

NCT01966289

A Pilot Study of SGI-110 in Combination With an Allogeneic Colon Cancer Cell Vaccine (GVAX) and Cyclophosphamide (CY) in Metastatic Colorectal Cancer (mCRC) as Maintenance Therapy

18

Dec 2019

NCT01319565

Prospective Randomized Study of Cell Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor Infiltrating Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction w/1200 TBI

102

Jun 2020

NCT02278887

Randomized Phase III Study Comparing a Non-myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Tumor Infiltrating Lymphocytes and Interleukin-2 to Standard Ipilimumab Treatment in Metastatic Melanoma

168

Sep 2020

Autologous dendritic cells

NCT00338377a

Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization

189

Feb 2019

NCT01204684

A Phase II Clinical Trial Evaluating Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen +/- Toll-like Receptor Agonists for the Treatment of Malignant Glioma

60

Oct 2019

Dendritic cells/cytokine-induced killer cells

NCT01691625a

Concurrent Chemoradiation With or Without DC-CIK Immunotherapy in Treating Locally Advanced Esophageal Cancer

50

Sep 2019

Tisagenlecleucel

NCT02445248

A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Individuals With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

116

Feb 2023

NCT02228096

A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Individuals With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia

64

Dec 2022

NCT02445222

Long Term Follow-Up of Individuals Exposed to Lentiviral-Based CD19 Directed CAR T-Cell Therapy

620

May 2035

Axicabtagene ciloleucel

NCT02601313

A Phase 2 Multicenter Study Evaluating Subjects With Relapsed/Refractory Mantle Cell Lymphoma (ZUMA-2)

130

Mar 2035

NCT02614066

A Study Evaluating KTE-C19 in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (r/r ALL) (ZUMA-3) (ZUMA-3)

100

Mar 2034

NCT02625480

A Multi-Center Study Evaluating KTE-C19 in Pediatric and Adolescent Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ZUMA-4)

100

Oct 2034

NCT03105336

A Phase 2 Multicenter Study of Axicabtagene Ciloleucel in Subjects With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5)

80

Mar 2034

 

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

ND Committee Review

Original Effective Date April 1, 2019

Internal Medical Policy Committee 5-19-2020 Policy updated with literature review through July 25, 2019; Sections regarding use of tisagenlecleucel and axicabtagene ciloleucel were removed and added to new policy 8.01.63 (Chimeric Antigen Receptor Therapy for Hemotologic Malignancies. Policy section revised to "All applications of adoptive immunotherapy evaluated in the policy are considered investigational."

Disclaimer

Current medical policy is to be used in determining a Member's contract benefits on the date that services are rendered. Contract language, including definitions and specific inclusions/exclusions, as well as state and federal law, must be considered in determining eligibility for coverage. Members must consult their applicable benefit plans or contact a Member Services representative for specific coverage information. Likewise, medical policy, which addresses the issue(s) in any specific case, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving and the Company reserves the right to review and update medical policy periodically.