Medical Policy: 08.01.26 

Original Effective Date: October 2017 

Reviewed: October 2017 

Revised: December 2017 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Adoptive Immunotherapy

Adoptive immunotherapy uses “activated” lymphocytes as a treatment modality. Both nonspecific and specific lymphocyte activation are used therapeutically. Nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.

 

T Lymphocytes and Killer Cells

Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin-2 (IL-2) and other cytokines. More recent techniques have yielded select populations of cytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with IL-2 and anti-CD3 antibody, a T-cell activator. Expansion of TIL for clinical use is labor intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment. Recently, cytokine-induced killer cells have been recognized as a new type of antitumor effector cells, which can proliferate rapidly in vitro, with stronger antitumor activity and a broader spectrum of targeted tumors than other reported antitumor effector cells.

 

Cellular Therapy and Dendritic Cell Infusions

The major research challenge in adoptive immunotherapy is to develop immune cells with antitumor reactivity in quantities sufficient for transfer to tumor-bearing patients. In current trials, 2 methods are studied: adoptive cellular therapy and antigen-loaded dendritic cell infusions.

 

Adoptive cellular therapy is “the administration of a patient’s own (autologous) or donor (allogeneic) anti-tumor lymphocytes following a lymphodepleting preparative regimen. Protocols vary, but include these common steps:

  1. Lymphocyte harvesting (either from peripheral blood or from tumor biopsy)
  2. Propagation of tumor-specific lymphocytes in vitro using various immune modulators
  3. Selection of lymphocytes with reactivity to tumor antigens with enzyme-linked immunosorbent assay
  4. Lymphodepletion of the host with immunosuppressive agents
  5. Adoptive transfer (ie, transfusion) of lymphocytes back into the tumor-bearing host

 

Dendritic cell-based immunotherapy uses autologous dendritic cells (ADC) (antigen presenting cells APCs) to activate a lymphocyte-mediated cytotoxic response against specific antigens in vivo. ADCs harvested from the patient are either pulsed with antigen presenting cells or transfected with a viral vector bearing a common cancer antigen. The activated ADCs are then retransfused into the patient, where they present antigen to effector lymphocytes (CD4-positive T-cells, CD8-positive T-cells, and in some cases, B cells). This initiates a cytotoxic response against the antigen and against any cell expressing the antigen. In cancer immunotherapy, ADCs are pulsed with tumor antigens; effector lymphocytes then mount a cytotoxic response against tumor cells expressing these antigens.

 

For the evidence review of dendritic cell based immunotherapy therapy (antigen presenting cells APCs – to include T-cells, B-cells, natural killer (NK) cells and other cells) for prostate cancer, see medical policy 08.01.27.

 

In an attempt to regulate the host immune system further, recent protocols use various cytokines (eg, IL-7 and IL-15 instead of IL-2) to propagate lymphocytes. Protocols also differ in the extent of host lymphodepletion induced prior to transfusing lymphocytes to the tumor-bearing host.

 

Note: Allogeneic cell transplantation following nonmyeloablative conditioning of the recipient (known as reduced-intensity conditioning) also may be referred to as “adoptive immunotherapy” in the literature. However, reduced-intensity conditioning cell transplantation relies on a donor-vs-malignancy effect of donor lymphocytes. In contrast, the adoptive immunotherapy techniques described in this evidence review enhance autoimmune effects primarily. The use of reduced-intensity conditioning in cell transplantation is discussed for specific cancers in individual policies related to cell transplantation.

 

Genetically Engineered T Cells

Engineered T-cell-based antitumor immunotherapy uses gene transfer of tumor antigen-specific T-cell receptors (TCR) or synthetic chimeric antigen receptors (CAR-T cells).

 

CAR-T Cell Therapy

Engineered T-cell based antitumor immunotherapy uses gene transfer of tumor antigen-specific T-cell receptors (TCR) or synthetic chimeric antigen receptors (CAR-T). CAR-T cells are prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard leukophoresis procedure. The blood is sent to the manufacturer where the mononuclear cells are enriched for T-cells. The T-cells are expanded in cell culture, washed, and formulated into a suspension, which is they cryopreserved. This process may take several weeks. The product is then infused into the patient. CAR-T cells can lead to severe adverse events shortly after infusion as well as at a later time, to include but not limited to cytokine-release syndrome (CRS) and neurological toxicities (headache, encephalopathy, delirium, anxiety, dizziness, aphasia and tremor).

 

Because of the risk of cytokine-release syndrome (CRS) and neurologic toxicities CAR-T cell therapy (Kymriah™ or Yescarta™) is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). The required components of REMS are:

  • Healthcare facilities that dispense and administer CAR-T cell therapy (Kymriah™ and/or Yescarta™) must be enrolled and comply with REMS requirements. Certified healthcare facilities must have on-site, immediate access to tocilizumab, and ensure that a minimum of two doses of toclizumab are available for each patient for infusion within 2 hours after Kymriah™ and/or Yescarta™, if needed for treatment of CRS.
  • Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer Kymriah™ or Yescarta™ are trained about the management of CRS and neurological toxicities.

 

Tisagenlecleucel (Kymriah™)

Tisagenlecleucel (Kymriah™) is an adoptive immunotherapy in which engineered T-cells uses gene transfer of synthetic chimeric antigen receptors (CAR-T cells). CAR-T cells are prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard leukophoresis procedure. The blood is sent to the manufacturer where the mononuclear cells are enriched for T-cells. The T-cells are expanded in cell culture, washed, and formulated into a suspension, which is they cryopreserved. This process may take several weeks. The product is then infused into the patient.

 

Tisagenlecleucel (Kymriah™) is a CD19-directed genetically modified autologous T-cell immunotherapy which involves reprogramming a patient’s a patient’s own T-cells with a transgene coding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. The CAR is comprised of a murine single-chain antibody fragment which recognizes CD19 and is fused to intracellular signaling domains from 4-1BB (CD137) and CD3 zeta. The CD3 zeta component is critical for initiating T-cell activation and antitumor activity, which 4-1BB (CD137) enhances the expansion and persistence of Kymriah™. Upon binding to CD19-expressing cells, the CAR transmits to promote T-cell expansion, activation, target cell elimination, and persistence of the Kymriah™ cells.

 

Tisagenlecleucel (Kymriah™) was approved on August 30, 2017, by the Food and Drug Administration (FDA) for the treatment of patients up through 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

 

Acute lymphoblastic leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is a malignancy (clonal) of the bone marrow in which the early lymphoid precursors of the white blood cells (called lymphoblasts) proliferate and replace the normal hematopoietic cells of the marrow. This results in overcrowding of the bone marrow, as well as the peripheral organs (particularly the liver, spleen, and lymph nodes) by the lymphoblasts. As a consequence, the leukemic blasts displace the normal hematopoietic bone marrow and cause cytopenias in all 3 cell lineages (anemia, thrombocytopenia, granulocytopenia). Leukostasis affecting brain and lung may also occur. Death occurs commonly due to severe pancytopenia and resulting infections. Refractory (resistant) disease is defined as those patients 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).

 

Approximately 5000 cases of B-cell ALL are diagnosed every year in the United States, and approximately 620 pediatric and young adult patients with B-cell ALL will relapse each year in the United States. It is largely a disease of the young with approximately 60% of cases occurring in patients younger than 20 years old with a median age at diagnosis of 15 years. While it is treatable in 85% cases, approximately 15% of children and young adults with ALL will relapse while 2% to 3% of ALL patients are primary refractory. Retreatment of refractory or relapsed ALL is generally unsuccessful and associated with a high mortality rate. The 2-year survival rate among patients with ALL who relapse after hematopoietic cell transplantation is 15%. The Food and Drug Administration approved clofarabine (as a single agent or in combination) in 2004 and blinatumomab in 2014 for relapsed and refractory ALL. Reported median objective response rates in the pivotal trials of the 2 agents were 19.7% and 33%, the median durations of response was 2.5 months and 6 months, and median overall survival durations were 3 months and 7.5 months, respectively. Note that the percentages of patients treated with 3 or more prior treatments of clofarabine and blinatumomab trial were 62% and 7%, respectively. Nevertheless, treatment options for patients with relapsed or refractory ALL are limited, associated with poor outcomes and high toxicity and the disease remains incurable.

 

Relapsed disease describes the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission. Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. MRD positivity is defined as the presence of 0.01% or more ALL cells and has been shown to be a strongest prognostic factor to predict the risk of relapse and death when measured during and after induction therapy in both newly diagnosed and relapsed ALL. In a 2017 meta-analysis of 20 studies of 11,249 pediatric ALL, the hazard ratio for event-free survival in MRD-negative patients compared with MRD-positive patients was 0.23 (95% confidence interval, 0.18 to 0.28).

 

Tisagenlecleucel (Kymriah™) is now a treatment option for patients up through age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.

 

Axicabtagene Ciloleucel (Yescarta™)

Axicabtagene ciloleucel (Yescarta™) is an adoptive immunotherapy in which engineered T-cells uses gene transfer of synthetic chimeric antigen receptors (CAR-T cells). CAR-T cells are prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard leukophoresis procedure. The blood is sent to the manufacturer where the mononuclear cells are enriched for T cells. The T cells are expanded in cell culture, washed, and formulated into a suspension, which is cryopreserved. This process may take several weeks. The product is then infused into the patient.

 

Axicabtagene ciloleucel (Yescarta™), a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T cell engagement with CD19-expressing target cells, the CD28 and CD3-zeta co-stimulating domains activate downstream signaling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells.

 

Axicabtagene ciloleucel (Yescarta™) was approved by the Food and Drug Administraiton (FDA) October 18, 2017 for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma (follicular lymphoma with histologic transformation to diffuse large B-cell lymphoma).

 

The FDA approval states that Axicabtagene ciloleucel (Yescarta™) is not indicated for the treatment of patients with primary central nervous system lymphoma. Primary Central nervous system (CNS) lymphoma is defined as a disease in which malignant cancer cells form in the lymph tissue of the brain and/or spinal cord. Because the eye is so close to the brain, primary CNS lymphoma can also start in the eye called ocular lymphoma.

 

Non-Hodgkin’s Lymphoma - Large B-Cell Lymphoma

Non-Hodgkin’s lymphoma (NHL) is a type of cancer that originates in lymphoid tissue and can spread to other organs. Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes or natural killer cells. In 2017, an estimated 72,240 people will be diagnosed with NHL and there will be approximately 20,140 deaths due to the disease.

 

NHL can be divided into two prognostic groups:

  • Indolent lymphomas: Grow slowly; considered low grade lymphomas
  • Aggressive lymphomas: Grow at a faster rate; considered high grade lymphomas

 

Sometimes lymphoma changes from a slow growing type into a faster growing type, this is knowns as transformation. The transformed lymphoma has to then be treated as a high grade lymphoma.

 

Non-Hodgkin’s lymphoma is called “high grade” when the cells appear to be dividing quickly. These may be called aggressive lymphomas.

 

Diffuse large B-cell lymphoma (DLBCL) are the most common lymphoid neoplasms in adults, accounting for approximately 32.5% of NHLs diagnosed annually. Subtypes include primary mediastinal large B-cell lymphoma, high grade B cell lymphoma and diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma (follicular lymphoma with histologic transformation to diffuse large B-cell Lymphoma).

  • Diffuse large B-cell lymphoma (DLBCL): The lymphoma cells look fairly large when seen with a microscope. DLBCL can affect people of any age. It usually starts as a quickly growing mass in the lymph node deep inside the body such as in the chest or abdomen, or in a lymph node such as in the neck or axilla. It may also start in other areas such as the intestines, bones or even the brain or spinal cord. DLBCL tends to be fast growing (aggressive) lymphoma.
  • Primary mediastinal large B-cell lymphoma (PMBL): PMBL is a distinct subtype of NHL that can be histologically indistinguishable from DLBCL that tends to occur in young adults with a median age of 35 years with a slight female predominance. PMBL arises from thymic B-cells with initial local regional spread to supraclavicular, cervical, hilar nodes and into the mediastinum and lung. Widespread extranodal disease is uncommon at initial diagnosis, present in approximately one quarter of patients, but can be more common at recurrence. Clinical symptoms related to rapid growth of mediastinal mass include superior vena cava (SVC) syndrome, pericardial and pleural effusions.
  • Diffuse large B-cell lymphoma (DLBCL) arising from follicular lymphoma – histological transformation to DLBCL: In patients with follicular lymphoma, histological transformation to DLBCL is generally associated with a poor clinical outcome. Histological transformation to DCBCL occurs at an annual rate of approximately 3% for 15 years and the risk of transformation falls after that time, for reasons that remain unclear. Follicular lymphoma is the most common subtype of indolent NHL. Usually this lymphoma occurs in many lymph nodes sites throughout the body, as well as in the bone marrow.

 

Defining Relapsed and Refractory Disease

Refractory (resistant) disease is suggested by a less than 50 percent decrease in lesion size with treatment in the absence of new lesion development. In contrast progressive disease usually manifests as the appearance of any new lesion, a 50 percent increase in the longest diameter of a previously identified lesion or new/recurrent involvement in the bone marrow. Relapsed disease reflects the appearance of any new lesion after attainment of an initial complete remission.

 

Refractory or progressive disease is identified during the post-treatment response evaluation. The majority of relapses occur during the first two years after completion of treatment. However, as many as 18 percent of relapses occur more than five years after initial treatment. Relapses are usually symptomatic and rarely identified solely on the basis of routine imaging. Progressive or relapse can present with systemic B symptoms (i.e. fever, night sweats, weight loss), cytopenias, the development of an extranodal mass, or as the symptomatic or asymptomatic enlargement of the lymph nodes, liver or spleen.

 

When relapse is suspected, a biopsy of the involved lymph node or mass is recommended to confirm relapse and evaluate a potential change in histology, for example indolent non-Hodgkin’s lymphoma to an aggressive non-Hodgkin’s lymphoma.

 

Treatment for Relapsed or Refractory Disease

Outcomes for patients with refractory diffuse large B-cell lymphoma (DLBCL) are poor.

 

Relapse or refractory diffuse large B-cell lymphomas is treated with systemic chemotherapy with or without rituximab with plans to proceed to high dose chemotherapy and hematopoietic stem cell transplantation (HCT) in those with chemotherapy sensitive disease. The treatment of patients who are not candidates for HCT, who fail to respond to second-line chemotherapy regimens, or who relapse after HCT is generally palliative.

 

In the absence of HCT, conventional chemotherapy regimens provide only transient disease control for the majority of patients with relapsed or refractory disease. Patients with primary refractory disease rarely achieve complete remission when treated with a second chemotherapy regimen. Following relapses from a first complete remission, a subset of patients will achieve a second complete remission with chemotherapy; however, these remissions are generally not durable, and long term disease free survivors are rare. In contrast, approximately half of patients who respond to a second chemotherapy regimen and proceed to HCT will maintain their response for two years.

 

Axicabtagene ciloleucel (Yescarta™) is now being considered as a treatment option for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma( follicular lymphoma with histologic transformation to diffuse large B-cell lymphoma). Axicabtagene ciloleucel (Yescarta™) is not indicated in the treatment of adult patients with primary central nervous system lymphoma.

 

Rationale

Assessment of efficacy for therapeutic intervention involves a determination of whether an intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes but are prone to biases such as non-comparability of treatment groups, placebo effect, and variable natural history of the condition.

 

Adoptive immunotherapy has been investigated for the treatment of relatively common cancers in which novel treatments have been adopted when randomized clinical trials show efficacy. The selected studies included only new randomized clinical trials.

 

Adoptive Immunotherapy Modalities

Three systematic reviews on adoptive immunotherapy combining studies using different adoptive immunotherapy methods have been published. Conditions treated in these reviews were renal cell carcinoma, and postoperative hepatocellular carcinoma.

 

Renal Cell Carcinoma
Cytotoxic Lymphocytes

Epstein-Barr Virus-Associated Cancers

 

Bollard et al (2014) conducted an international prospective cohort study of cytotoxic T lymphocytes (CTL) therapy in patients with Epstein-Barr virus (EBV)-positive Hodgkin or non-Hodgkin lymphoma. Patients had either active, relapsed disease (n=21) or were in remission with a high risk of relapse (n=29). CTLs with activity against EBV antigens were generated by incubating peripheral blood monocytes with EBV antigen-infected dendritic cells. Eleven (52%) of 21 patients with active disease achieved complete response (CR), and 2 (10%) patients achieved partial response; 2-year event-free survival in this cohort was approximately 50%. Twenty-seven (93%) of 29 patients in remission achieved CR; 2-year event-free survival was 82%. Immediate or delayed toxicity related to CTL infusion was not observed.

 

Chia et al (2014) studied 35 patients with EBV-positive nasopharyngeal cancer at a single center in China. Patients received standard chemotherapy with gemcitabine and carboplatin followed by EBV-specific CTL infusion. Median progression-free survival (PFS) and overall survival (OS) were 8 months and 30 months, respectively. One-, 2-, and 3-year OS rates were 77%, 63%, and 37%, respectively. In comparison, median OS in a group of similar historical controls treated at the same institution with chemotherapy only was 18 to 21 months, and 2- and 3-year OS rates were 30% to 43% and 16% to 25%, respectively. The most common adverse events associated with CTL infusion were grade 1 and 2 fatigue and grade 1 myalgia. Two patients developed transient fever, and 3 patients developed grade 1 skin rash. Grade 3 or higher hematologic or nonhematologic toxicities were not observed during CTL therapy. In a 2014 Japanese series of 7 patients who received CTLs for advanced oral and maxillofacial cancers, 1-year survival in patients who achieved response (n=3) and in those with progressive disease (n=4) were 100% and 25%, respectively, although definitions of response were unclear.

 

Summary: Epstein-Barr Virus-Associated Cancers

Two small, prospective noncomparative cohort studies in patients with relapsed disease indicated response to infused CTLs directed against cancer-associated viral antigens. Adverse events were mild or moderate. There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in EBV-associated cancers. To establish efficacy, the following is needed: large, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Cytomegalovirus-Associated Cancers

Schuessler et al (2014) administered CTLs with or without chemotherapy to 13 patients with recurrent glioblastoma multiforme. CTLs with activity against Cytomegalovirus were generated by incubating peripheral blood monocytes with synthetic peptide epitopes. Median OS was 1.1 years (range, 4.4 months to 6.6 years). Adverse events were minor.

 

Summary: Cytomegalovirus-Associated Cancers

A single case series in 13 patients with glioblastoma multiforme treated with CTL has been published. Adverse events were mild. There are no RCTs comparing CTL with standard of care and therefore no conclusions can be made about the efficacy of CTL in Cytomegalovirus-associated cancers. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Cytokine-Induced Killer Cells

Nasopharyngeal Carcinoma

Li et al (2012) conducted an RCT to evaluate the efficacy of autologous cytokine-induced killer (CIK) transfusion in combination with gemcitabine and cisplatin (GC) chemotherapy to treat nasopharyngeal carcinoma in patients with distant metastasis after radiotherapy. From 2007 to 2008, 60 patients with distant metastasis after radiotherapy were followed in a university cancer center in China. Patients were randomized to 2 groups; 30 patients in the GC plus CIK group received adoptive autologous CIK cell transfusion in combination with GC chemotherapy, and 30 patients in the GC group received chemotherapy alone. One- and 2-year OS rates were 90% (27/30) and 70% (21/30), respectively, in the GC plus CIK group vs 83% (25/30) and 50% (15/30), respectively, in the GC group. Mean OS was 31 months for the GC plus CIK group and 26 months for the GC group (p=0.137). Median PFS was 26 months for the GC plus CIK group and 19 months for the GC group (p=0.023). This small, single-center RCT indicates that the combination of CIK cells and GC regimen chemotherapy may be a viable treatment option for patients with advanced nasopharyngeal carcinoma.

 

Summary: Nasopharyngeal Carcinoma

A single RCT from China reported numerically favorable but statistically insignificant effect on PFS and OS. This body of evidence is limited by the context of the studies (non-U.S.), small sample size, and other methodologic weaknesses (inadequate reporting of randomization, allocation concealment, and power). To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Renal Cell Carcinoma

Liu et al (2012) conducted an RCT to evaluate the effects of autologous CIK cell immunotherapy in patients with metastatic renal cell carcinoma followed up in another university cancer center in China. From 2005 to 2008, 148 patients were randomized to autologous CIK cell immunotherapy (arm 1, n=74) or IL-2 treatment combination with human interferon- α-2a (arm 2, n=74). The primary end point was OS, and the secondary end point was PFS evaluated by Kaplan-Meier analyses and hazard ratios (HRs) with Cox proportional hazards models. Three-year PFS and OS rates in arm 1 were 18% and 61%, respectively, vs 12% and 23%, respectively, in arm 2 (p=0.031 and <0.001, respectively). Median PFS and OS in arm 1 were significantly longer than those in arm 2 (PFS, 12 vs 8 months, p=0.024; OS, 46 vs 19 months, p<0.001). Multivariate analyses indicated that the cycle count of CIK cell immunotherapy as a continuous variable was significantly associated with prolonged PFS (HR=0.88; 95% CI, 0.84 to 0.93; p<0.001) and OS (HR=0.58; 95% CI, 0.48 to 0.69; p<0.001) in arm 1. These findings suggest that CIK cell immunotherapy has the potential to improve the prognosis of patients with metastatic renal cell carcinoma.

 

Zhang et al (2013) conducted a small RCT in China with 20 patients who had unilateral, locally advanced renal cell carcinoma after nephrectomy. Patients were randomized 1:1 to postoperative CIK therapy or usual care (chemotherapy with or without radiotherapy, additional surgery, or no further treatment). Method of randomization was not described. At a median follow-up of 44 months, 6 patients in the CIK group and 5 controls achieved CR; 2 patients in the CIK group and no controls achieved partial response (overall objective response, 80% vs 50% in the CIK and control groups, respectively; p=0.175). Mean PFS was significantly longer in the CIK group, but OS was not (mean PFS, 32 months vs 22 months; p=0.032; mean OS, 35 months vs 34 months; p=0.214). Adverse events included mild arthralgia, laryngeal edema, fatigue, and low-grade fever in 3 patients. Grade 3 or higher adverse events were not observed.

 

Zhao et al (2015) conducted an RCT in China among operable and inoperable patients with renal cell carcinoma. Dendritic cells were also incorporated into treatment. Among the 60 operable patients, the 3-year disease-free survival (DFS) rate was 96.7% compared with 57.7% in the control group. PFS was also better in the CIK group (p=0.021). Among the 62 inoperable patients, OS was better in the CIK group (p=0.012). No severe adverse reactions were observed.

 

Summary: Renal Cell Carcinoma

Three RCTs from China have evaluated the efficacy of CIK cell immunotherapy in renal cell carcinoma. The largest of the 3 RCTs reported statistically significant gain in PFS and OS with CIK cell immunotherapy compared with interleukin-2 (IL-2) plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The remaining 2 RCTs also reported response rate in favor of CIK therapy with inconsistent effect on survival. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Gastric Cancer

In 2012, Shi et al in China published a nonrandomized, comparative study to determine the long-term efficacy of adjuvant immunotherapy with autologous CIK cells in 151 patients with locally advanced gastric cancer. Five-year OS and 5-year DFS rates for immunotherapy vs no immunotherapy (control group) were 32% vs 23% (p=0.07) and 28% vs 10% (p=0.04), respectively. For patients with intestinal-type tumors, 5-year OS (47% vs 31%; p=0.045) and DFS (42% vs 16%; p=0.02) rates were significantly higher for immunotherapy.

 

Subsection Summary: Gastric Cancer

A single nonrandomized prospective study from China has reported statistically significant effects on DFS and OS in favor of immunotherapy with autologous CIK vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Colorectal Cancer

Zhao et al (2016) reported the results of a controlled trial in which 122 patients with metastatic colorectal cancer were randomized to CIK cell immunotherapy plus chemotherapy (n=61) or chemotherapy alone (n=61). The primary study end point was OS. The median OS was significantly greater with CIK cell immunotherapy plus chemotherapy (36 months) than with chemotherapy alone (16 months; p<0.001). The 3-year OS rates for both groups were 48% and 23%, respectively (p<0.001).

 

Summary: Colorectal Cancer

A single RCT from China has reported a statistically significant effect on OS in favor of immunotherapy with CIK immunotherapy vs chemotherapy alone. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Hepatocellular Carcinoma

Cai et al (2017) reported the results of a meta-analysis of 9 RCTs and 3 quasi-RCTs that compared outcomes of conventional treatments plus sequential CIKs with conventional treatments alone (total N=1387 patients). None of the 12 studies were rated as low risk of bias in all 7 domains as assessed by the Cochrane risk of bias tool. Of the 12 RCTs and quasi-RCTs, 5 reported a statistically significant favorable survival benefit for patients receiving conventional treatments plus sequential CIKs. All 12 studies were from Asia (1 Japan, 1 Korea, 10 China). Results of meta-analysis reported a statistical significant reduction in the hazard of death by 41% (HR=0.59; 95% CI, 0.46 to 0.77; p<0.005). However, the heterogeneity among the included studies was statistically significant (p=0.03, I2=48).

 

Yu et al (2014) conducted an RCT in China of 132 patients who had previously untreated hepatocellular carcinoma. Patients were randomized 1:1 to CIK therapy plus standard treatment (surgical resection in eligible patients, local treatment, or best supportive care) or standard treatment only. At a median follow-up of 19 months, median PFS was 14 months in the CIK group and 7 months in the control group (p=0.019). Estimated 1-, 2-, and 3-year PFS rates were 56% vs 35% (p=0.004), 36% vs 18% (p=0.004), and 27% vs 18% (p=0.017), respectively. Median OS was 25 months in the CIK group vs 11 months in the control group (p=0.008). Estimated 1-, 2-, and 3-year OS rates were significantly higher for immunotherapy: 74% vs 50% (p=0.002), 53% vs 30% (p=0.002), and 42% vs 24% (p=0.005), respectively. In the subgroup of operable patients, 3-year and median OS did not differ statistically between groups. Common adverse events attributed to CIK therapy were grade 1 or 2 fever, allergy, and headache. Grade 3 or 4 adverse events were not observed. A 2014 nonrandomized study from China reported improved PFS in 30 patients who received radiofrequency ablation plus CIK/natural killer cell/gamma delta T-cell (a type of tumor-infiltrating lymphocytes [TIL]) infusion (median PFS, not reached) compared with 32 patients who received radiofrequency ablation alone (median PFS, 12.0 months).

 

Lee et al (2015) conducted an RCT in Korea of 230 patients being treated for hepatocellular carcinoma by surgical resection, radiofrequency ablation, or percutaneous ethanol injection. Patients were randomized 1:1 to adjuvant CIK cell injections 16 times during 60 weeks or to no adjuvant therapy. The primary end point was recurrence-free survival; secondary end points included OS and cancer-specific survival. The median recurrence-free survival was 44 months in the CIK group and 30 months in the control group (p=0.010). OS was longer in the CIK group than in the control group (HR=0.21, p=0.008). Cancer-specific survival was longer in the CIK group than in the control group (HR=0.19, p=0.02). Adverse events occurred more frequently in the CIK group than in the control group, but grade 3 or 4 adverse events did not differ significantly between groups. Adverse events associated with CIK included pyrexia, chills, myalgia, and fatigue.

 

Summary: Hepatocellular Carcinoma

Several RCTs and quasi-RCTs have evaluated the efficacy of CIK cells in hepatocellular cancers. These studies have generally reported some benefits in response rates and/or survival. Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death by 41%, but there was considerable heterogeneity among the included studies. Most trials were from Asia and did not use standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Non-Small-Cell Lung Cancer

Wang et al (2014) conducted a systematic review of RCTs of CIK cells for the treatment of non-small-cell lung cancer (NSCLC). Overall, 17 RCTs (total N=1172 patients) were included in the analysis. The studies generally had small sample sizes; the largest had 61 CIK-treated patients and 61 control patients. Most studies also incorporated dendritic cell therapy. All were conducted in China. A significant effect of CIK was found for median time to progression and median survival time. OS at various time points significantly favored CIK.

 

Summary: Non-Small-Cell Lung Cancer

A single systematic review of RCTs of CIK cells for the treatment of NSCLC that included trials conducted in China reported some benefits in median time to progression and median survival time. The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Tumor-Infiltrating Lymphocytes

Melanoma

Dudley et al (2008) conducted a series of nonrandomized phase 2 studies examining TIL plus IL-2 in patients with metastatic melanoma under various conditions of preinfusion lymphodepletion. A non-myeloablative 7-day chemotherapy regimen (n=43) was compared with ablative regimens comprising 5-day chemotherapy plus either 200 centigray (cGy; n=25) or 1200 cGy (n=25) total-body irradiation. Ninety-five percent of patients had progressive disease after prior systemic treatment. Objective response rates by Response Evaluation Criteria in Solid Tumors were 49%, 52%, and 72%, respectively, and did not differ significantly among groups. Responses occurred at multiple metastatic sites, including the brain, and many were durable; 10 patients who achieved CR had no relapse at a median follow-up of 31 months. Toxicities of treatment occurred primarily in the 1200-cGy group and included a delay in marrow recovery of 1 to 2 days compared with the other treatment groups, somnolence requiring intubation, renal insufficiency, and posterior uveitis. Rosenberg et al (2011) reported updated results of these patients with median follow-up of 62 months.30 Ten patients who previously had been classified as partial responders were reclassified as complete responders by Response Evaluation Criteria in Solid Tumors (1, 3, and 6 patients in the non-myeloablative, 200-cGy, and 1200-cGy groups, respectively). Of these 20 patients (22% of the original cohort), 19 (95%) had ongoing complete regression longer than 3 years. Actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders, 100% and 93%, respectively. Likelihood of achieving a CR was similar regardless of prior therapy.

 

Dreno et al (2002) conducted an RCT of 88 patients with malignant melanoma without detectable metastases who were randomized to TIL plus IL-2 or to IL-2 alone. There was no significant difference in the duration of relapse-free interval or OS. Figlin et al (1999) randomized 178 patients with metastatic renal cell carcinoma or resectable renal tumors to adjuvant continuous low-dose IL-2 therapy, with or without additional TIL. TILs were harvested from surgical specimens. Outcomes were similar in both groups and, for this reason, the trial was terminated early.

 

Subsection Summary: Melanoma

One small RCT compared TILs plus IL-2 with IL-2 alone in patients with nonmetastatic melanoma and reported no difference between treatment groups in relapse or survival outcomes. Cohort studies in patients with refractory metastatic melanoma demonstrated response rates of 49% and 52% to 72% with TIL plus nonmyeloablative or myeloablative regimens, respectively. Durable responses in the majority of patients who achieved CR were observed beyond 3 years. Toxicities appeared primarily associated with myeloablative regimen. Larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and use of appropriate standard of care as control arm showing treatment benefit are needed to establish.

 

Dendritic Cells

For the evidence review of dendritic cell based immunotherapy therapy (antigen presenting cells APCs – to include T-cells, B-cells, natural killer (NK) cells and other cells) for prostate cancer, see medical policy 08.01.27.

 

Antigen-loaded autologous dendritic cells (ADCs) have been explored primarily in early-stage trials in various malignancies including lymphoma, myeloma, subcutaneous tumors, melanoma, NSCLC, renal cell cancer, and cervical cancer. A 2012 systematic review highlighted progress in dendritic cellbased immunotherapy in epithelial ovarian cancer.

 

Glioblastoma Multiforme

In 2013, Bregy et al published a systematic review of observational studies of active immunotherapy using ADCs in the treatment of glioblastoma multiforme. Twenty-one studies published through early 2013 were included in this review (total N=403 patients). Vaccination with dendritic cells loaded with autologous tumor cells resulted in an increased median OS in patients with recurrent disease (72-138 weeks across 8 studies), as well as in those newly diagnosed (65-230 weeks across 11 studies) compared with average survival of 58 weeks. Complications and safety of the vaccine were assessed in all studies. No study indicated any sign of autoimmune reaction. Most adverse events were injection-site reactions (22%). Other adverse events included fatigue (19.5%), constipation/diarrhea (1.6%), myalgia/malaise (1.6%), shivering (1.4%), and vomiting (0.5%).

 

Summary: Glioblastoma Multiforme

A systematic review of observational studies has examined the role of ADC-based adoptive immunotherapy in glioblastoma multiforme. Because of the observational and noncomparative nature of the available evidence, the review is subject to publication and selection bias, which has the potential to lessen or amplify the true potential of adoptive immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Non-Small-Cell Lung Cancer

Shi et al (2012) conducted an RCT at a university cancer center in China to evaluate the role of dendritic cell (DC)/CIK combination immunotherapy as maintenance treatment of advanced NSCLC. From 2008 to 2010, 60 patients with stage IIIB or IV disease after treatment with 4 cycles of a platinum-based chemotherapy regimen were randomly divided into 2 groups. One group was treated with DC/CIK cell therapy (n=30), and the other was a control group who received no adoptive immunotherapy (n=30). Outcome measures were PFS and adverse events of treatment/toxicity. PFS was 3.2 months in the DC/CIK group (95% CI, 2.9 to 3.5 months) vs 2.6 months control group (95% CI, 2.39 to 2.73 months; p<0.05). No significant toxic reactions were observed in the DC/CIK group, including bone marrow toxicity and gastrointestinal reactions. The findings of this small single-center RCT indicate that combination immunotherapy with dendritic cells and CIK cells may offer a viable option as maintenance therapy for patients with advanced NSCLC.

 

Chen et al (2014) in China conducted a systematic review and meta-analysis of RCTs that compared DC/CIK combination immunotherapy with any other treatment (placebo, no intervention, conventional treatment, or other complementary and alternative medicines) for any cancer type and stage. Two included RCTs that compared DC/CIK plus chemotherapy with chemotherapy alone in patients with stage III or IV NSCLC reported OS estimates (total N=150). Pooled relative risk (RRs) favored DC/CIK therapy at 2 years but not at 1 year (RR for 1-year OS=1.38; 95% CI, 1.00 to 1.90; p=0.05; I2=35%; RR for 2-year OS=2.88; 95% CI, 1.38 to 5.99; p=0.005; I2=0%).

 

The 2014 systematic review by Wang (discussed previously) also included many studies that used DC in combination with CIK.

 

Summary: Non-Small-Cell Lung Cancer

Two RCTs and a meta-analysis of these RCTs have evaluated the efficacy of DC/CIK cells in NSCLC. The RCTs have generally reported some benefits in response rates and/or survival. Results of meta-analysis of these trials also reported a statistical significant reduction in the hazard of death. However, the effect was inconsistent. Most were from Asia and did not use standard of care as control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Medullary Thyroid Cancer

In a 2009 phase 1 pilot study, 10 patients with metastatic medullary thyroid cancer (MTC) were treated with ADCs pulsed with allogeneic MTC tumor cell lysate. At median follow-up of 11 months, 3 (30%) patients had stable disease, and 7 (70%) patients progressed. No World Health Organization grade 3 or 4 toxicities or autoimmune reactions were observed. Of note, human leukocyte antigen match between patients and tumor cell lines did not predict disease stabilization or progression, suggesting that, should future studies demonstrate efficacy of ADC therapy for MTC using allogeneic tumor lysate, an unlimited source of tumor material may be available for lysate preparation.

 

Summary: Medullary Thyroid Cancer

A small prospective noncomparative study in 10 MTC patients with treated with ADCs has been published. There are no RCTs comparing dendritic cell based adoptive immunotherapy with standard of care and therefore no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Pancreatic Cancer

A 2009 phase 1 study of 5 patients with inoperable pancreatic cancer reinfused ADCs and lymphokine-activated killer cells with gemcitabine; antigen priming of the ADCs was presumed to occur in vivo from apoptosis of gemcitabine-exposed tumor cells. One patient had a partial response, two had stable disease for more than 6 months, and 2 patients had disease progression. Toxicities included grade 1 anemia and grade 2 leukocytopenia, nausea, and constipation.

 

Summary: Pancreatic Cancer

A small prospective noncomparative study in 5 patients with pancreatic cancer treated with ADCs and lymphokine-activated killer has been published. There are no RCTs comparing dendritic cellbased adoptive immunotherapy with standard of care and therefore no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight and the use of an appropriate standard of care as the control arm showing treatment benefit.

 

Genetically Engineered T Cells

Review articles have highlighted recent progress in this field for solid and hematologic malignancies.

 

TCR Therapy

In a phase 2 study, Johnson et al (2009) transfected autologous peripheral lymphocytes of 36 patients who had metastatic melanoma with genes encoding TCRs highly reactive to melanoma/melanocyte antigens (MART-1:27-35 and gp100:154-162). Nine (25%) patients experienced an objective response; 8 patients had a partial response lasting 3 months to more than 17 months; and 1 patient (in the gp100 group) had a complete response lasting more than 14 months. Treatment toxicities included erythematous rash, anterior uveitis, hearing loss, and dizziness, suggesting that these were attributable to recognition by the genetically modified lymphocytes of normally quiescent cells expressing the targeted cancer antigens; melanocytic cells exist in the skin, eye, and the inner ear. Ideal targets for TCR gene therapy may be antigens that arise in cancers of nonessential organs (e.g. prostate, ovary, breast, thyroid) or are not expressed on normal adult tissues (e.g. cancer-testes antigens).

 

Additional studies have examined TCR gene therapy in Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma.

 

Summary: TCR Therapy

One small cohort study in patients with metastatic melanoma reported a 25% response rate with TCR gene therapy and broad treatment-related toxicities. This evidence does not demonstrate net health benefit with genetically engineered T cells in patients with metastatic melanoma.

 

CAR-T Cell Therapy

Tisagenlecleucel (Kymriah™)
Pivotal Trial

In the pivotal trial phase 2 single-arm, international, multicenter trial (study B2202), 68 patients ages 3 to 21 years at screening, with CD19-positive second or greater bone marrow relapse or primary refractory B-cell acute lymphoblastic leukemia were treated with tisagenlecleucel and followed for 12 months. This trial has not been published; information was obtained from the Food and Drug Administration Oncologic Drugs Advisory Committee Meeting held in July 2017. Sixty-three patients received U.S.-manufactured product while 5 patients received EU-manufactured product. Patients were required to have more than 5% blasts at screening and either ineligible for, or have relapsed after, allogeneic cell transplant. Refractory was defined by not achieving an initial CR after 2 cycles of a standard chemotherapy regimen (primary refractory). Subjects who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemo-refractory.

 

The prespecified primary efficacy end point was the proportion of patient who achieved objective remission rate (ORR; CR or CR with incomplete blood count recovery [CRi]) as assessed by an independent review committee within 3 months after tisagenlecleucel infusion. The trial would meet its primary objective if the lower bound of the 2-sided 95% confidence intervals for ORR was greater than 20%. The key secondary outcome was proportion of patients who achieve best ORR (CR or CRi with an minimal residual disease [MRD]–negative bone marrow) within 3 months of receiving tisagenlecleucel. Key secondary end points were tested sequentially (after primary end point was significant) to control for overall type I error.

 

Of 107 patients who were screened, 88 met the trial inclusion criteria and of these 68 (77.3%) were infused with tisagenlecleucel. In 7 (8%) patients, tisagenlecleucel could not be manufactured. The median time from enrollment to infusion was 44 days. Of the 68 patients, 63 patients received tisagenlecleucel infusion at least 3 months prior to the data cutoff date. Patients received investigator choice bridging chemotherapy as needed to control their leukemia while waiting for tisagenlecleucel infusion. Patients also received protocol mandated lymphocyte-depleting chemotherapy 2 to 14 days prior to tisagenlecleucel infusion. The median age was 12 years (range, 3-23 years), 82% were male, 75% were white, median Karnofsky/Lansky Performance Status score was 90 (range, 50-100), 79% had relapsed disease, 12% had chemo-refractory disease, and 9% had primary refractory disease. The enrolled patient population was heavily pretreated as evident by the following statistics; 87% (59) of patients had received a prior hematopoietic cell transplant with a median of 3 previous treatments. Results summarized in Table 1 show that 52 (82.5%) patients who received tisagenlecleucel infusion achieved a CR or CRi within 3 months. Of the 52 patients who achieved a CR or CRi within 3 months, 29 (56%) were still in remission,13 (25%) had relapsed, 12 (23%) were censored prior to the data cutoff. The reasons for censoring were six received hematopoietic cell transplant, five received a new cancer therapy, and one was lost to follow-up. The estimated relapse-free rate among responders at month 6 was 75.4% (95% CI, 57.2% to 86.7%). Among the responders, four died (three after disease relapse, one after new cancer therapy was initiated while in remission).

 

Table 1. Summary of Efficacy Results of the Pivotal Study
OutcomesResults, n (%) (95% confidence interval) or %
N 63
Primary end point (3 mo)
Objective remission rate (CR + CRi) 52 (82.5) (70.9 to 91.0)
CR 40 (63)
CRi 12 (19)
Not reported/unknown 11 (17.5)
Secondary end point (3 mo)
Best objective remission rate (Cr + CRi with MRD-positive) 52 (82.5) (70.9 to 91.0)
Other secondary end points
Median duration of remission Not reached
Median event-free survival Not reached
Percent relapse-free at 6 mo after remission 75
Percent survival at 6 mo 89
Percent survival at 9 mo 79
Percent survival at 12 mo 79

CR: complete remission; CRi: complete remission with incomplete blood count recovery; MRD: minimal residual disease.

 

Supportive Studies

Two single-arm studies that included a total of 84 patients were conducted using product manufactured at University of University of Pennsylvania cell and vaccine production facility. The first study was a phase 1/2a single-center study in 55 patients enrolled between March 2012 and November 2015. The ORR rate (CR or CRi) was 95% (52/55), and best ORR (CR or CRi with MRD-negative bone marrow) was 89% (49/55). Median OS was 32.7 months (95% CI, 21.0 to inestimable). First pediatric patient treated in the study has been in remission for 5 years. The second study was a phase 2 multicentric study that enrolled 29 patients between August 2014 and February 2016. The ORR rate (CR or CRi) was 69% (20/29).

 

Safety

Safety data included 68 patients (63 patients received who U.S.-manufactured product plus 5 patients who received EU-manufactured product) and is summarized in Tables 2 and 3.55,56 Cytokine release syndrome (CRS) was the most common serious life-threatening adverse event in the pivotal study and required aggressive supportive measures. One fatality due to CRS-related coagulopathy was observed in the pivotal study. Any grade CRS occurred in 78% (53/68) patients while 47% (32/68) experienced a grade 3 or 4 CRS. The severity of CRS was associated with high tumor burden of greater than 50% blasts in the bone marrow at screening. CRS occurred after a median of 3 days (range, 1-22 days) after tisagenlecleucel infusion and lasted for a median duration of 8 days. CRS resulted in significant morbidity burden as indicated by intensive care unit admission (31 [46%]), ventilatory support (10 [15%]), dialysis (7 [10%]), hypotension (35 [51%]), and hypotension requiring high-dose vasopressor support (17 [25%]).

 

The next most important adverse event of tisagenlecleucel was neurotoxicity such as encephalopathy and seizures. Any grade neurotoxicity was reported in 44% (30/68) patients, and grade 3 neurotoxicity was reported in 15% (10/68) patients. No cases of grade 4 neurotoxicity were reported. Although neurotoxicity was reversible with the use of optimal and best supportive care, the severity of these toxicities requires monitoring for airway protection.

 

The Food and Drug Administration also noted infection as a special adverse event of interest. In the first 8 weeks after infusion, 43% (29/68) of patients developed infection of which 24% (16/68) were grade 3 and 3% (2/68) were grade 4. Infection included gram-positive, gram-negative systemic infections, Clostridium difficile, candida, herpes simplex, and encephalitis due to herpesvirus 6. Three deaths occurring within 60 days and related to infection with herpesvirus 6, bacterial infection, and fungal sepsis was reported.

 

Other adverse events of special interest included prolonged cytopenia, cardiac disorders, and B-cell aplasia. Three patients experienced congestive heart failure that required treatment. Most patients in the pivotal trial had previously been treated with chemotherapy and radiotherapy that predisposed them to cardiotoxicity; it is an anticipated risk in the intended population that would receive treatment with tisagenlecleucel. Acquired hypogammaglobulinemia is an expected side effect of tisagenlecleucel because it not only kills pre-B acute lymphoblastic leukemia cells but also normal B cells because they are CD19-positive. Patients in the trial were maintained on supplemental treatment with intravenous gamma globulin after tisagenlecleucel. It is unclear as to how long intravenous gamma globulin would be required.

 

Multiple design features of the tisagenlecleucel retroviral vector such as minimal homology between packaging plasmids and vector sequences, segregation on 4 different DNA plasmids, deletion of HIV accessory genes, and use of “self-inactivating” vector design aim to reduce the risk the potential of replication competent virus generation and insertional mutagenesis. However, the theoretical risk of formation of replication competent virus, their clonal growth or neoplastic transformation of transduced cells cannot be ruled out. If approved each vector batch and production cells will be tested for the presence of replication competent retrovirus. However, Novartis does not plan to collect patient samples for replication competent retrovirus testing. It is expected that over next 5 years, approximately 5000 patients may be enrolled in the first 5 years in a postmarketing registry that will follow-up patients up to 15 years after tisagenlecleucel infusion.

 

Table 2. Summary of Serious Adverse Events (>5% Patients) in the Pivotal Study
Serious Adverse EventaResults, n (%)
N 68
Cytokine release syndrome 43 (63)
Febrile neutropenia 14 (21)
Hypotension 8 (12)
Acute kidney injury 5 (7)
Fever 5 (7)
Hypoxia 4 (6)

aAny adverse event that resulted in death or was life-threatening or required inpatient hospitalization or caused prolongation of existing hospitalization or resulted in persistent or significant disability/incapacity or was a congenital anomaly/birth defect, or required intervention to prevent permanent impairment or damage.

 

Table 3. Summary of Adverse Events of Special Interest in 68 Patients in the Pivotal Study
Adverse EventsGrade 3, n (%)aGrade 4, n (%)bAll Grades, n (%)
Patients with at least 1 event 23 (34) 28 (41) 62 (91)
Cytokine release syndrome 14 (21) 18 (27) 53 (78)
Febrile neutropenia 23 (34) 2 (3) 25 (37)
Hematopoietic cytopenia not resolved by day 28 10 (15) 12 (18) 25 (37)
Infections 16 (24) 2 (3) 29 (43)
Transient neuropsychiatric events 10 (15) 0 30 (44)
Tumor lysis syndrome 3 (4) 0 3 (4)

aSevere or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care.

bLife-threatening consequences; urgent intervention indicated.

 

Summary: Tisagenlecleucel (KymriahTM)

Observed outcomes in a single-arm study design cannot be attributed solely to the intervention itself because they could occur as a result of a placebo effect, the natural course of the disease, or confounding by time-varying factors. However, it is unlikely that the 83% response rate (measured by CR or CRi) seen in the pivotal single-arm trial of tisagenlecleucel in patients with relapsed or refractory acute lymphoblastic leukemia could be the result of non-interventional effect. An unbiased estimate of the safety of tisagenlecleucel cannot be ascertained from this evidence base because of the lack of control arm, which makes it difficult to determine whether the observed adverse reactions are a consequence of background disease or the drug itself. However, tisagenlecleucel is a biologic drug and therefore observed adverse reactions that have immunologic basis are likely drug-mediated. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. CRS was observed in more than half (63%) of the patients and approximately 40% had an adverse event at grade 4 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting.

 

Axicabtagene ciloleucel (Yescarta™)
Pivotal Trial

The approval for axicabtagene ciloleucel (Yescarta™) is supported by data from the ZUMA-1 pivotal trial. The ZUMA-1 study is a phase 1/2, single arm, open-label study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Eligible patients must have had all of the following: 1) histologically confirmed diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), or transformation follicular lymphoma (TFL); 2) chemotherapy refractory disease, defined as one or more of the following: progressive disease or stable disease lasting ≤ 6 months, as best response to most recent chemotherapy regimen; or disease progression or recurrence ≤  12 months after prior ASCT), if salvage therapy is given post ASCT, the subject must have had no response to or relapsed after the first line of therapy; 3) prior therapy must have included at a minimum: an anti-CD20 monoclonal antibody containing regimen (unless tumor is CD20 negative) and an anthyracycline-containing chemotherapy regimen; for patients with transformed follicular lymphoma must have received prior chemotherapy for follicular lymphoma and subsequent refractory disease after transformation to DLBCL; 4) at least one measurable lesion per revised International Working Group (IWG) Response Criteria; 5) no evidence of CNS lymphoma by magnetic resonance imaging; and 6) ≥ 2 weeks since prior radiation therapy or systemic therapy at the time of leukophoresis. Eligible patients are also aged ≥ 18 years, with ECOG performance status of 0 or 1, absolute neutrophil count of ≥ 1,000/uL, absolute lymphocyte count >100/uL and platelet count of ≥ 75,000/uL. Patient must have had adequate renal, hepatic, and cardiac function defined as creatinine clearance >60 mL/min, serum ALT/AST of  ≤ 2.5 times the upper limit of normal, total bilirubin of ≤ 1.5 mg/Dl (except in patients with Gilbert’s syndrome), cardiac ejection fraction of ≥ 50%, and no evidence of pericardial effusion, as determined by an echocardiogram (ECHO), and baseline oxygen saturation >92% on room air. Key exclusion criteria included history of malignancy other than non-melanoma skin cancer or carcinoma in-situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years, ASCT within 6 weeks of informed consent, history of allogeneic hematopoietic stem cell transplant, prior CAR therapy or other genetically modified T cell therapy or history or presence of CNS disorder such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease or any autoimmune disease with CNS involvement. All patients provided written, informed consent. The Institutional Review Board/Independent Ethics Committee of each study site approved the protocol.

 

Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma (NHL) in the United States, accounting for approximately 30%-40% of cases of NHL. Studies examining outcomes in patients with relapsed/refractory DLBCL show that the response rates to subsequent therapy varies from 14% to 63%. However, relapse/refractory DLBCL is broadly defined and consists of a heterogeneous patient population. Outcomes are particularly poor in those patients with truly refractory DLBCL, defined as no response to last line of chemotherapy or relapse within 1 year of autologous stem cell transplant (ASCT). A large patient level meta-analysis of patients with refractory DLBCL (Retrospective Non-Hodgkin Lymphoma Research, SCHOLAR-1) found that outcomes in this homogenous population are significantly worse, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival (OS) of 6.6 months, indicating a major unmet need for effective therapies in these patients.

 

Adoptive cell therapy with T-cells genetically engineered to express chimeric antigen receptor (CAR) targeting CD19 is a promising approach for treatment of B cell malignancies. The following information is based on the ZUMA-1 trial evaluating the safety and efficacy of anti-CD19 CAR T cells in patients with refractory non-Hodgkin’s lymphoma (NHL) (NCT02348216) and what the FDA approval is based on:

 

Following lymphodepleting chemotherapy, YESCARTA™ was administered as a single intravenous infusion at a target dose of 2 × 106 CAR-positive viable T cells/kg (maximum permitted dose: 2 × 108 cells). The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m2 intravenously and fludarabine 30 mg/m2 IV, both given on the fifth, fourth, and third day before YESCARTA™. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. All patients were hospitalized for YESCARTA™ infusion and for a minimum of 7 days afterward.

 

Of 111 patients who underwent leukapheresis, 101 received YESCARTA™. Of the patients treated, the median age was 58 years (range: 23 to 76), 67% were male, and 89% were white. Most (76%) had DLBCL, 16% had transformed follicular lymphoma, and 8% had primary mediastinal large B-cell lymphoma. The median number of prior therapies was 3 (range: 1 to 10), 77% of the patients had refractory disease to a second or greater line of therapy, and 21% had relapsed within 1 year of autologous HSCT.

 

One out of 111 patients did not receive the product due to manufacturing failure. Nine other patients were not treated, primarily due to progressive disease or serious adverse reactions following leukapheresis. The median time from leukapheresis to product delivery was 17 days (range: 14 to 51 days), and the median time from leukapheresis to infusion was 24 days (range: 16 to 73 days). The median dose was 2.0 × 106 CAR-positive viable T cells/kg (range: 1.1 to 2.2 × 106 cells/kg).

 

Efficacy was established on the basis of complete remission (CR) rate and duration of response (DOR), as determined by an independent review committee (Table 5 and Table 6). The median time to response was 0.9 months (range: 0.8 to 6.2 months). Response durations were longer in patients who achieved CR, as compared to patients with a best response of partial remission (PR) (Table 6). Of the 52 patients who achieved CR, 14 initially had stable disease (7 patients) or PR (7 patients), with a median time to improvement of 2.1 months (range: 1.6 to 5.3 months).

 

Table 4. Response Rate
Rate TypeRecipients of YESCARTA (N = 101)
Objective Response Ratea 73 (72%)
(95% CI)
(62, 81)
Complete Remission Ratea 52 (51%)
(95% CI)
(41, 62)
Partial Remission Ratea 21 (21%)
(95% CI)
(13, 30)

CI, confidence interval.

aPer 2007 revised International working Group criteria, as assessed by the independent review committee.

 

Table 5. Duration of Response
Number of RespondersFrom N of 101 (N = 73)
DOR (Months)a
Medianb
9.2
(95% CI)
(5.4, NE)
Range
0.4, 14.4+
DOR if Best Response is CR (Months)
Medianb
NE
(95% CI)
(8.1, NE)
Range
0.4, 14.4+
DOR if Best Response is CR (Months)
Medianb
2.1
(95% CI)
(1.3, 5.3)
Range
0.03+, 8.4+
Median Follow-up for DOR (Months)a,b 7.9

CR, complete remission; DOR, duration of response; NE, not estimable; PR, partial remission.

aAmong all responders. DOR is measured from the date of first objective response to the date of progression or death from relapse or toxicity.

bKaplan-Meier estimate

cA + sign indicates a censored value.

 

The most common grade 3 or higher adverse events included anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%) and decreased lymphocyte count (20%). As compared to the interim analysis, grade 3 or higher cytokine release syndrome decreased from 18% to 13% and neurologic events decreased from 34% to 28%. There were no cases of cerebral edema.

 

As previously reported at the American Society of Hematology Annual Meeting in 2016, there were three deaths not due to disease progression in the study. Two events, one hemophagocytic lymphohistiocytosis and one cardiac arrest in the setting of CRS, were deemed related to axicabtagene ciloleucel. The third case, a pulmonary embolism, was deemed unrelated. Between the interim analysis that included 62 patients, and the primary analysis which includes all 101 patients, there were no additional deaths due to adverse events.

 

Summary: Axicabtagene ciloleucel (Yescarta™)

The approval for axicabtagene ciloleucel (Yescarta™) is supported by data from the ZUMA-1 pivotal trial. The ZUMA-1 study is a phase 1/2, single arm, open-label study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in a 101 patients with refractory/relapsed aggressive non-Hodgkin lymphoma (NHL) (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma and transformed follicular lymphoma). The study met the primary endpoint of objective response rate (ORR), or rates of tumor response (complete response + partial response) recorded after a single infusion of axicabtagene ciloleucel (Yescarta™) with 82%. The complete remission rate after treatment with axicabtagene ciloleucel (Yescarta™) was 51%. This FDA approval brings an additional treatment option for these patients with few other options that have not responded to previous treatments. Also, the observed benefits seen with axicabtagene ciloleucel (Yescarta™) were offset by a high frequency and severity of adverse reactions. In an interim analysis, grade 3 or higher cytokine release syndrome (CRS) decreased from 18% to 13% and neurologic events decreased from 34% to 28%. Due to the risk of CRS and neurologic toxicities, axicabtagene ciloleucel (Yescarta™) was approved with a risk evaluation and mitigation strategy (REMS), which includes elements of safe use. To further evaluate the long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with axicabtagene ciloleucel (Yescarta™).  The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

 

Summary Of Evidence

Cytotoxic T Lymphocytes

For individuals with Epstein-Barr virus associated cancers who receive cytotoxic T lymphocytes, the evidence includes 2 small, prospective noncomparative cohort studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The cohort studies have shown a treatment response to infused cytotoxic T lymphocytes directed against cancer-associated viral antigens. To establish efficacy, the following is needed: large, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with Cytomegalovirus-associated cancers who receive cytotoxic T lymphocytes, the evidence includes a single case series. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. In the absence of an RCT comparing cytotoxic T lymphocytes with standard of care, no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Cytotoxic-Induced Killer Cells

For individuals with nasopharyngeal carcinoma who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The RCT reported a numerically favorable but statistically insignificant effect on progression-free survival and overall survival. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with renal cell carcinoma who receive CIK cells, the evidence includes multiple RCTs. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The largest of the RCTs reported statistically significant gains in progression-free survival and overall survival with CIK cellbased immunotherapy compared with interleukin-2 plus interferon-α-2. This body of evidence is limited by the context of the studies (non-U.S.) and choice of a nonstandard comparator. The other 2 RCTs have also reported response rates in favor of CIK therapy with inconsistent effect on survival. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with gastric cancer who receive CIK cells, the evidence includes a single nonrandomized prospective study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The prospective cohort study reported statistically significant effect on disease-free survival and overall survival in favor of immunotherapy vs no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with colorectal cancer who receive CIK cells, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of the RCT showed a statistically significant effect on overall survival in favor of immunotherapy vs chemotherapy alone. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with hepatocellular carcinoma who receive CIK cells, the evidence includes several RCTs. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Several RCTs from Asia have generally reported some benefits in response rates and/or survival. The results of a meta-analysis of these trials have also shown a statistically significant 41% reduction in the hazard of death, but there was considerable heterogeneity across the included studies. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with non-small-cell lung cancer who receive CIK cells, the evidence includes multiple RCTs and a systematic review. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A single systematic review of RCTs reported some benefits in median time to progression and median survival time. The included body of evidence trials in the systematic review is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Tumor-Infiltrating Lymphocytes

For individuals with melanoma who receive tumor-infiltrating lymphocytes, the evidence includes a single RCT. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Results of a small RCT have reported no difference in relapse or survival outcomes. Cohort studies in patients with refractory metastatic melanoma have demonstrated response rates of 49% with immunotherapy and 52% to 72% with no immunotherapy. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Dendritic Cells

For individuals with glioblastoma multiforme who receive dendritic cells, the evidence includes a systematic review of observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Because of the observational and noncomparative nature of the available evidence, it is difficult to draw any meaningful conclusions. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with non-small-cell lung cancer who receive dendritic cells, the evidence includes 2 RCTs and a meta-analysis. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The RCTs have generally reported some benefits in response rates and/or survival. The results of a meta-analysis of these trials also reported a statistical significant reduction in the hazard of death. Most trials were from Asia and did not use standard of care as the control arm. This body of evidence is limited by the context of the studies (non-U.S.), small sample sizes, heterogeneous treatment groups, and other methodologic weaknesses. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with medullary thyroid cancer who receive dendritic cells, the evidence includes one prospective noncomparative study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. A small prospective noncomparative study in 10 medullary thyroid cancer patients treated with autologous dendritic cells has been published. There are no RCTs comparing dendritic cellbased adoptive immunotherapy with standard of care and, therefore, no conclusions can be made. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For individuals with pancreatic cancer who receive dendritic cells, the evidence includes a small prospective noncomparative study. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The study reported on treatment outcomes for 5 patients with pancreatic cancer. Because of the noncomparative nature of the available evidence and small sample base, it is difficult to draw any meaningful conclusions. To establish efficacy, the following is needed: larger, well-conducted, multi-centric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

For the evidence review of dendritic cell based immunotherapy therapy (antigen presenting cells APCs – to include T-cells, B-cells, natural killer (NK) cells and other cells) for prostate cancer, see medical policy 08.01.27.

 

Genetically Engineered T Cells

Peripheral T Lymphocytes

For individuals with cancers who receive autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors, the evidence includes multiple small observational studies. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. Multiple observational studies have examined autologous peripheral T lymphocytes containing tumor antigen-specific T-cell receptors in melanoma, Hodgkin and non-Hodgkin lymphoma, prostate tumors, and neuroblastoma. Because of the noncomparative nature of the available evidence with a small sample size, it is difficult to draw any meaningful conclusion. To establish efficacy, the following is needed: larger, well-conducted, multicentric trials with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as the control arm showing treatment benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.

 

Tisagenlecleucel (Kymriah™)

For individuals who are 3 to 25 years of age with relapsed or refractory B-cell acute lymphoblastic leukemia who receive tisagenlecleucel, the evidence includes multiple single-arm prospective trials. Relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related mortality and morbidity. The pivotal single-arm trials reported an 83% response rate (measured by complete response or complete remission with incomplete blood count) in heavily pretreated patients. All patients who achieved a complete remission or complete remission with incomplete blood count were also minimal residual diseasenegative, which is predictive of survival in acute lymphoblastic leukemia patients. After a median follow-up of 4.8 months, the median duration of response was not reached. The observed benefits seen with tisagenlecleucel were offset by a high frequency and severity of adverse reactions. Cytokine release syndrome was observed in more than half (63%) of the patients, and approximately 40% had an adverse event at grade 4 or higher. Long-term follow-up and real-world evidence is required to assess the generalizability of tisagenlecleucel efficacy and safety outside of a clinical trial setting. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

 

Axicabtagene ciloleucel (Yescarta™)

The approval for axicabtagene ciloleucel (Yescarta™) is supported by data from the ZUMA-1 pivotal trial. The ZUMA-1 study is a phase 1/2, single arm, open-label study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in a 101 patients with refractory/relapsed aggressive non-Hodgkin lymphoma (NHL) (including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma and transformed follicular lymphoma). The study met the primary endpoint of objective response rate (ORR), or rates of tumor response (complete response + partial response) recorded after a single infusion of axicabtagene ciloleucel (Yescarta™) with 82%. The complete remission rate after treatment with axicabtagene ciloleucel (Yescarta™) was 51%. This FDA approval brings an additional treatment option for these patients with few other options that have not responded to previous treatments. Also, the observed benefits seen with axicabtagene ciloleucel (Yescarta™) were offset by a high frequency and severity of adverse reactions. In an interim analysis, grade 3 or higher cytokine release syndrome (CRS) decreased from 18% to 13% and neurologic events decreased from 34% to 28%. Due to the risk of CRS and neurologic toxicities, axicabtagene ciloleucel (Yescarta™) was approved with a risk evaluation and mitigation strategy (REMS), which includes elements of safe use. To further evaluate the long-term safety, the FDA is requiring the manufacturer to conduct a post-marketing observational study involving patients treated with axicabtagene ciloleucel (Yescarta™).  The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

 

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

Acute Lymphoblastic Leukemia (ALL) Version 4.2017

Current NCCN guidelines for acute lymphoblastic leukemia recommend (category 2A) tisagenlecleucel as a treatment option for:

  • Ph-positive patients 25 years or less in age with refractory disease or 2 or greater relapses and failure of 2 tyrosine kinase inhibitors.
  • Ph-negative patients 25 years or less in age with refractory disease or 2 or greater relapses.

 

Head and Neck Cancers Version 2.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Kidney Cancer (Renal Cell Carcinoma) Version 1.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Gastric Cancer Version 5.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Colon Cancer Version 2.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Rectal Cancer Version 3.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Hepatobiliary Cancers Version 4.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option for hepatocellular carcinoma.

 

Non-Small Cell Lung Cancer Version 9.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Melanoma Version 1.2018

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Central Nervous System Cancers Version 1.2017
Glioblastoma Multiforme

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Thyroid Carcinoma Version 2.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Pancreatic Adenocarcinoma 3.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Bladder Cancer Version 5.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

B-Cell Lymphomas Version 5.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option, however the discussion section is showing an update is in progress to correspond with newly updated algorithm.

 

Hodgkin Lymphoma Version 1.2017

NCCN guideline does not include recommendations for adoptive immunotherapy as a treatment option.

 

Regulatory Status

Adoptive immunotherapy is not a U.S. Food and Drug Administration-regulated procedure.

 

On August 30, 2017, tisagenlecleucel (Kymriah™; Novartis) was approved by the Food and Drug Administration (FDA) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

 

On October 18, 2017, axicabtagene ciloleucel (Yescarta™, Kite Pharma, Inc.) was approved by the Food and Drug Administration (FDA) for the treatment of adult patients 18 years and older with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

 

Prior Approval:

 

Prior approval required.

 

Policy:

See also Medical Policy 08.01.27 Cellular Immunotherapy for Prostate Cancer – Provenge (Sipuleucel-T)

 

Adoptive immunotherapy using any one of the following is considered investigational for all indications:

  • Adoptive cellular therapy for the administration of cytotoxic T-lymphocytes
  • Cytokine-induced killer cells, tumor-infiltrating lymphocytes
  • Antigen-loaded autologous dendritic cells (antigen presenting cells APCs) (except for prostate cancer, see medical policy 08.01.27)
  • Genetically engineered T-cells except as indicated below for CAR-T cell therapy

 

CAR-T Cell Therapy

Tisagenlecleucel (Kymriah™) 

(See also Policy Guidelines below)

 

Tisagenlecleucel (Kymriah™) intravenous infusion is considered medically necessary for relapsed or refractory patients 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% lymphoblasts); AND
  • Are 25 years old or younger at the time of infusion; AND
  • Have not received prior treatment with tisagenlecleucel or any other gene therapy or are being considered for treatment with any other gene therapy; AND
  • Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis; AND
  • 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
    • Active central nervous system disease
      • Patients with central nervous system 2 disease [cerebrospinal fluid containing blasts, but <5 white blood cells per microliter] are eligible

 

Definitions:

Relapsed 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 stem cell transplant.

 

Refractory (resistant) disease is defined as those patients 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).

 

Tisagenlecleucel (Kymriah™) is considered investigational for all other indications not listed above as the safety and efficacy has not yet been established in the peer reviewed medical literature.

 

Axicabtagene ciloleucel (Yescarta™) 

Axicabtagene ciloleucel (Yescarta™) intravenous infusion is considered is considered medically necessary for patients meeting all of the following criteria:

  • Adult patients 18 years and older
  • Histologically confirmed large B-cell lymphoma including:
    • Diffuse large B-cell lymphoma (DLBCL) to include DLBCL not otherwise specified; or
    • High grade B-cell lymphoma (aggressive type); or
    • Primary mediastinal large B-cell lymphoma (PMBCL); or
    • Transformation follicular lymphoma (TFL) (DLBCL arising from follicular lymphoma); AND 
  • Is relapsed or refractory disease after two or more lines of systemic therapy (defined as no response to last line of therapy; or disease progression or recurrence ≤ 12 months after prior autologous stem cell transplant (ASCT); if salvage therapy is given post ASCT, the subject must have had no response to or relapsed after the first line of therapy); AND
  • Patients must have received prior therapy including at a minimum:
    • Anti-CD20 monoclonal antibody (unless tumor is CD20 negative); AND
    • An anthracycline containing chemotherapy regimen
    • For patients with transformed follicular lymphoma (TFN) must have received prior chemotherapy for follicular lymphoma and subsequently have chemo-refractory disease after transformation to diffuse large B-cell lymphoma (DLBCL); AND
  • At least one measurable lesion per revised International Working Group (IWG) response criteria (> 1.5 cm in any axis; or increase by ≥ 50% of previously involved sites from nadir); AND
  • Absolute neutrophil count (ANC) ≥  1000/uL; AND
  • Absolute lymphocyte count (ALC) > 100/uL; AND
  • Platelet Count ≥ 75,000/uL: AND
  • Adequate renal, hepatic, pulmonary and cardiac function defined as:
    • Creatinine clearance > 60 mL/min
    • Serum ALT/AST <2.5 times the upper limit of normal
    • Total bilirubin <15. mg/dl, except in subjects with Gilbert’s syndrome
    • Cardiac ejection fraction > 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant pleural effusion
    • Baseline oxygen saturation > 92% on room air; AND
  • Do not have any of the following:
    • Patients with detectable cerebrospinal fluid malignant cells, or brain metastases, or with history of primary central nervous system lymphoma (CNS lymphoma), cerebrospinal fluid malignant cells or brain metastases.
    • History of malignancy other than nonmelanoma skin cancer or carcinoma in-site (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years.
    • Prior CAR therapy or other genetically modified T-cell therapy.
    • Presence of fungal, bacterial, viral or other infection that is uncontrolled requiring IV antimicrobials for management (simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment).
    • Known history of infection with HIV or hepatitis B (HBsAG positive) or hepatitis C virus (anti-HCV positive); a history of hepatitis B or hepatitis C is permitted if the viral load is undetectable per quantitative PCR and/or nucleic acid testing).
    • History of presence of CNS disorders such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.

 

Axicabtagene ciloleucel (Yescarta™) is considered investigational for all other indications not listed above as the safety and efficacy has not yet been established in the peer reviewed medical literature.

 

Policy Guidelines

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

 

The recommended dosage of tisagenlecleucel (Kymriah™) for patients 50 kg or less is 0.2 to 5.0×106 chimeric antigen receptor-positive viable T cells per kg body weight intravenously; for patients above 50 kg, dose is 0.1 to 2.5 x 108 total chimeric antigen receptor positive viable T cells (non-weight-based) intravenously.

 

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

  • CNS 1: No lymphoblasts in the cerebrospinal fluid (CSF), regardless of the white blood cell (WBC) count
  • CNS 2: A white blood cell (WBC) count of less than 5 leukocytes/mcL in the cerebral spinal fluid (CSF) with the presence of blasts
  • CNS 3: A white blood cell (WBC) count of 5 leukocytes/mcL or greater with the presence of blasts

The recommended dosage of axicabtagene ciloleucel (Yescarta™) comprises a suspension of 2 x 106 CAR-positive viable T-cells per kg of body weight, with a maximum of 2 x 108 CAR-positive viable T-cells in approximately 68 mL.

 

Tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) has a black box warning because of the risk of cytokine release syndrome and neurologic toxicities that include fatal or life-threatening reactions. It should not be administered to patients with active infection or inflammatory disorders. It is recommended that severe or life-threatening cytokine release syndrome should be treated with tocilizumab. Patients should be monitored for neurologic events after treatment.

 

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

  • Health care facilities that dispense and administer tisagenlecleucel (Kymriah) and/or axicabtagene ciloleucel (Yescarta™) 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 patient for administration within 2 hours after tisagenlecleucel (Kymriah™) and/or axicabtagene ciloleucel (Yescarta™) infusion, if needed for treatment of cytokine release syndrome (CRS).
  • Certified health care facilities must ensure that health care providers who prescribe, dispense or administer tisagenlecleucel (Kymriah™) and/or axicabtagene ciloleucel (Yescarta™) are trained about the management of cytokine release syndrome (CRS) and neurologic toxicities.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 38999 Unlisted procedure hemic or lymphatic system
  • C9399 Unclassified drugs or biologics
  • J3590 Unclassified biologics
  • S2107 Adoptive immunotherapy i.e. development of specific antitumor reactivity (e.g. tumor-infiltrating lymphocyte therapy) per course of treatment
  • Q2040 Tisagenlecleucel, up to 250 million car-positive viable T-cells, including leukapheresis and dose preparation procedures, per infusion (Kymriah™)

 

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Policy History:

  • December 2017 - Interim Review, Policy Revised
  • October 2017 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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