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                                        • Contrasting the evidence from pivotal trials with the real world evidence (RWE)

                                        Contrasting the evidence from pivotal trials with the real world evidence (RWE)

                                        Adobestock-202377709-von-connect-world-klein1
                                        Research area: High tech medicine

                                        Project team ALL: Andrea Titieni-Schuhmann, Anja Panhuber
                                        Project team DLCBL & PMBCL: Anja Panhuber, Gregor Götz
                                        Duration: April 2022 – November 2022
                                        Language: English with German summary

                                        Publication: HTA Project Report No. 146: https://eprints.aihta.at/1415/

                                        Background: Various malignant diseases of the hematopoietic system arise from malignant B cells. Depending on the site of origin of the degenerated B cells, a differentiation is made between the various types of blood cancer. Acute lymphoblastic leukemia (ALL) is a disease of the lymphoid cells from the bone marrow, approximately 75% of ALL is caused by degenerate B cells (B cell ALL) [1]. Diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) belong to the non-Hodgkin's lymphomas (NHL) and are malignancies that usually arise in the lymph nodes [2, 3]. Through the blood or lymphatic system, the malignant B cells can eventually spread throughout the body and affect other organs.

                                        The mentioned blood cancers are considered to be particularly aggressive and lead to death within months if left untreated. ALL occurs mainly in children under five years of age, with an incidence of 5.3 per 100,000 children per year (Germany) [4]. While DLBCL frequently affects older people over 70 years of age, PMBCL occurs more frequently in young women between 30 and 40 years of age. DLBCL is one of the most common NHLs, with an incidence of 5-7 per 100,000 population [5, 6], while PMBCL is a rare disease, accounting for 2-4 percent of all NHLs [7]. However, the actual incidence of PMBCL is controversial, the prevalence is 1-9 cases per 100,000 people [8].

                                        Chemotherapy is the standard treatment in the first and second line, often in combination with stem cell transplantation [4, 6]. However, not all patients are suitable for or respond to stem cell therapy. For this reason, intensive research is conducted to find new therapeutic approaches for these patients. These include, among others, genetic engineering methods, like the so-called CAR-T cell therapies (Chimeric Antigen Receptor). [9]. In 2018, the European Medicines Agency (EMA) approved two of these CAR-T cell therapies, axicabtagen ciloleucel (Yescarta®, Kite Pharma) and tisagenlecleucel (Kymriah®, Novartis), as orphan drugs for relapsed or refractory B-cell ALL, DLBCL, or PMBCL after two or more lines of therapy [10, 11].

                                        For treatment with CAR T cells, the patient's own T cells are removed and genetically altered in order to express a new receptor (CAR) on their cell surface. This receptor can bind to antigens on the cell surface of tumor cells. The modified CAR-T cells can thus recognize and specifically eliminate cancer cells in the body. The extracted T cells are multiplied in the laboratory and returned to the patient's body [12]. According to the European Society for Blood and Marrow Transplantation (EBMT) Annual Report (2021), 2,750 patients have been treated with CAR-T cell therapies to date [13].

                                        Due to the small number of patients and the resulting small cohorts in the pivotal studies, an analysis of the patient-relevant benefit and safety by comparing the results of post-approval studies as well as registry studies is needed. Initial systematic studies of the beneficial effects of CAR-T cell therapies in DLBCL have already been conducted in 2020 and are updated in this report [14].

                                        Table 1: Therapy (line) recommendations according to guidelines

                                        Treatment strategy for ALL

                                        Source: AWMF[1]

                                        First line therapy

                                        Chemotherapy

                                        .. in the case of a significantly increased risk of recurrence

                                        Allogenic HSCT

                                        .. with CNS involvement

                                        Radiation therapy

                                        Relapse

                                         

                                        Unfavorable risk profile

                                        Induction therapy + allogenic HSCT

                                        Favorable risk profile

                                        Induction therapy + chemotherapy

                                        Bone marrow recurrence

                                        CD3/19 AB Blinatumomab

                                        CNS/testicular involvement

                                        Local radiation

                                         

                                        Treatment strategy for DLBCL

                                        Source: Onkopedia[2], Completion of the AWMF guideline in July 22

                                        First line therapy

                                        R-CHOP

                                        Relapse

                                         

                                        Younger patients

                                        High dose therapy (chemotherapy) with autologous stem cell transplantation (autoSCT)

                                        Older patients

                                        Immunochemotherapy

                                        2. Relapse

                                        alloSCT, CAR-T, palliation

                                         

                                        Treatment strategy for PMBCL

                                        Source: Onkopedia2

                                        First line therapy

                                        R-CHOP

                                        Relapse

                                         

                                        Younger patients

                                        High dose therapy (chemotherapy) with autologous stem cell transplantation (autoSCT)

                                        Older patients

                                        Immunochemotherapy

                                        2. Relapse

                                        alloSCT, CAR-T, palliation

                                        Project aims and research questions: The primary aim of this project is to systematically synthesize the evidence from health care studies (RWE: observational and registry studies) on the use of CAR-T cell therapies since their approval in 2018, and to compare the results from pivotal studies and health care studies regarding patient characteristics, efficacy/safety endpoints. Instead of a separate HTA, a summary of the results of HTAs - based on the pivotal studies - is given.

                                        The following research questions result from the defined objectives:

                                        1. RQ1: What are the results of HTAs regarding the available evidence (clinical trials) and their critical evaluation of approved CAR-T cell therapies:
                                          1. Kymriah® in r/r B cell acute lymphoblastic leukemia (B ALL), children, adolescents and young adults up to and including 25 years of age.
                                          2. Yescarta® or Kymriah® in adult patients with r/r diffuse large B cell lymphoma (DLBCL) with at least two prior systemic therapies.
                                          3. Yescarta® in adult patients r/r with primary mediastinal large B-cell lymphoma (PMBCL) with at least two prior systemic therapies.
                                        2. RQ2: What are the differences in patient characteristics, efficacy, and safety in the results of pivotal studies and in health care studies (observational and registry studies) regarding therapy with
                                          1. Kymriah® in r/r B cell acute lymphoblastic leukemia (B ALL), children, adolescents and young adults up to and including 25 years of age.
                                          2. Yescarta® or Kymriah® in adult patients with r/r diffuse large B cell lymphoma (DLBCL) with at least two prior systemic therapies.
                                          3. Yescarta® in adult patients r/r with primary mediastinal large B-cell lymphoma (PMBCL) with at least two prior systemic therapies.

                                        Methods: Derived from the research questions presented, this project consists of three parts.

                                        Part 1: Health Technology Assessments (HTAs) on the approved CAR-T cell therapies Yescarta® and Kymriah® (Anja Panhuber)

                                        Method RQ1: Hand search and systematic summary of assessments from (selected) national HTA institutions for health policy decision making regarding reimbursement of CAR-T cell therapies, highlighting patient populations (with greatest benefit), prior therapies and co-medication, etc.:

                                        Table 2: HTA reports from selected HTA institutions.

                                         

                                        Yescarta® (DLBCL, PMBCL)

                                        Kymriah® (DLBCL)

                                        Kymriah® (ALL)

                                        IQWiG/ GBA

                                        Dossier evaluation:

                                        • https://bit.ly/3y24fmx (DLBCL)
                                        • https://bit.ly/38uYzGA (PMBCL)

                                        Benefit assessment:

                                        https://bit.ly/3OFI4bG

                                        Dossier evaluation:

                                        https://bit.ly/3xTe06b   

                                        Benefit assessment:

                                        https://bit.ly/3OyOetU

                                        Dossier evaluation:

                                        https://bit.ly/3LofIQW

                                        Benefit assessment:

                                        https://bit.ly/37GAbSF

                                        CADTH

                                        https://bit.ly/3Lg6I0h

                                        https://bit.ly/3EP34It

                                        NICE

                                        https://bit.ly/3KlZWVF

                                        https://bit.ly/3vkJ8tI

                                        https://bit.ly/3LkEamn

                                        ICER

                                        https://bit.ly/3xYgYGQ

                                        Part 2: Approved CAR-T cell therapies in children, adolescents and young adults up to 25 years of age with r/r B-cell acute lymphoblastic leukemia (ALL) (Andrea Titieni-Schuhmann, Anja Panhuber)

                                        Method RQ2: For the systematic review, a systematic literature search and an extended hand search (registry studies) are conducted. After selection of the literature, the data will be extracted and then summarized to answer research questions 1 and 2. All steps (literature selection, data extraction, quality assessment) will be performed by two authors (ATS & AP) using the 4-eyes principle.

                                        Criteria for systematic search/inclusion criteria ALL:

                                        Population

                                        Patients with refractory or relapsed acute lymphoblastic leukemia (children and adolescents aged 3 to 25 years)

                                        Intervention

                                        CAR-T cell therapy with Kymriah®/ Tisagenlecleucel (independent of previously administered therapy).

                                        NOT:

                                        • Alternative, not yet approved (CD-19) CAR-T cell therapies and dual-target CAR-T cell therapies (e.g., anti-CD19/CD22/CD20).
                                        • Studies in which allogeneic (donor-derived CAR-T) and non-autologous CAR-T were used

                                        Control

                                        Standard treatment without CAR-T cell therapy

                                        Outcomes

                                        Effectiveness:

                                        • Overall survival ? 6 months of FU
                                        • Life quality
                                        • Progression free survival ? 6 months of FU
                                        • Overall response, complete/partial response

                                        Safety:

                                        • Serious adverse events (cytokin release syndrome (CRS), neurologic toxicities, cytopenia, SAE)
                                        • Other adverse events (AE)

                                        NOT:

                                        • Studies using only surrogate endpoints

                                        Study design

                                        • (Non) Randomized Control Trials (nRCTs/RCTs)
                                        • Retrospective studies
                                        • Prospective case series with ? 5 patients
                                        • Registry studies
                                        • Other observational studies with real world evidence

                                        Publication period

                                        2018 until 03/2022

                                        Language

                                        German, English

                                        Part 3: Approved CAR-T cell therapies in adult patients with r/r diffuse large B cell lymphoma (DLBCL) and with r/r primary mediastinal large B cell lymphoma (PMBCL) (Anja Panhuber, Gregor Götz)

                                        Method: For the systematic review, a systematic literature search and an extended hand search (registry studies) are conducted. After selection of the literature, the data will be extracted and then summarized to answer research questions 1 and 2. All steps (literature selection, data extraction, quality assessment) will be performed by two authors (AP & GG) using the four-eyes principle.

                                        Criteria for systematic search/inclusion criteria DLBCL/PMBCL:

                                        Population

                                        Adult patient (? 18 years) with

                                        1. relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) after two or more systemic therapies
                                        2. relapsed or refractory primary mediastinal B-cell lymphoma (r/r PMBCL) after two or more systemic therapies

                                        Intervention

                                        CAR-T cell therapies with

                                        • Axicabtagen-ciloleucel (Yescarta®) or Tisagenlecleucel (Kymriah®), regardless of previously administered therapy - (r/r DLBCL)
                                        • Axicabtagen-ciloleucel (Yescarta®), regardless of previously administered therapy - (r/r PMBCL)

                                        NOT:

                                        • Alternative, not yet approved (CD-19) CAR-T cell therapies and dual-target CAR-T cell therapies (e.g., anti-CD19/CD22/CD20).
                                        • Studies in which allogeneic (donor-derived CAR-T) and non-autologous CAR-T were used

                                        Control

                                        Standard treatment without CAR-T cell therapy

                                        1. Systemic relapse therapy: allogenic HSCT, palliation
                                        2. Systemic relapse therapy: allogenic HSCT, palliation

                                        Outcomes

                                        Effectiveness:

                                        • Overall survival after ? 3 months (r/r DLBCL), resp. ? 6 months (r/r PMBCL) follow-up (FU)
                                        • Life quality
                                        • Progression free survival after ? 3 months (r/r DLBCL), resp. ? 6 months (r/r PMBCL) FU
                                        • Overall response, complete/partial response

                                        Safety:

                                        • Serious adverse events (cytokin release syndrome (CRS), neurologic toxicities, cytopenia, SAE)
                                        • Other adverse events (AE)

                                        NOT:

                                        • Studies using only surrogate endpoints

                                        Study design

                                        • (Non) Randomized Control Trials (nRCTs/RCTs)
                                        • Retrospective studies
                                        • Prospective case series with ? 10 patients for DLBCL; ? 5 patients for PMBCL
                                        • Registry studies
                                        • Other observational studies with real world evidence

                                        NOT:

                                        • Studies where data on r/r DLBCL/ PMBCL patients were not published separately for this group

                                        Publication period

                                        until 05/2022

                                        Language

                                        German, English

                                        Schedule and milestones:

                                        Time period

                                        Task

                                        Part 1: HTAs on the approved CAR-T cell therapies Yescarta® and Kymriah®

                                        April 2022

                                        Hand search on HTAs

                                        May – June 2022

                                        Systematic summary of HTAs: differences and similarities in critical appraisal

                                        July 2022

                                        Internal Review

                                        Part 2: Contrasting registration studies with data from care studies ALL

                                        April 2022

                                        Systematic literature search (search, abstract screening), hand search

                                        May 2022

                                        Data analysis (data extraction & control, quality assessment & control)

                                        June 2022

                                        Report preparation (background, method, results, discussion)

                                        July 2022

                                        Internal Review

                                        Part 3: Contrasting the registration studies with data from care studies DLBCL and PMBCL

                                        April 2022

                                        Scoping (literature review, background, project protocol, define the research question)

                                        May 2022

                                        Systematic literature search (search, abstract screening), hand search

                                        June – July 2022

                                        Data analysis (data extraction & control, quality assessment & control)

                                        August – mid September 2022

                                        Report preparation (background, method, results, discussion)

                                        15.09.2022

                                        Continuous text completed

                                        End of September 2022

                                        Internal Review

                                        Mid October 2022

                                        External Review

                                        Mid October – Mid November 2022

                                        Revision, finalisation, publication

                                        15.11.2022

                                        Final report

                                        References:

                                        [1]     Huang F.-L., Liao E.-C., Li C.-L., Yen C.-Y. and Yu S.-J. Pathogenesis of pediatric B-cell acute lymphoblastic leukemia: Molecular pathways and disease treatments. Oncology letters. 2020;20(1):448-454. Epub 2020/05/04. DOI: 10.3892/ol.2020.11583.

                                        [2]     Li S., Young K. H. and Medeiros L. J. Diffuse large B-cell lymphoma. Pathology. 2018;50(1):74-87. Epub 2017/11/24. DOI: 10.1016/j.pathol.2017.09.006.

                                        [3]     Martelli M., Ferreri A., Di Rocco A., Ansuinelli M. and Johnson P. W. M. Primary mediastinal large B-cell lymphoma. Critical Reviews in Oncology/Hematology. 2017;113:318-327. DOI: https://doi.org/10.1016/j.critrevonc.2017.01.009.

                                        [4]     Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. (AWMF). Akute lymphoblastische Leukämie - ALL - im Kindesalter. 2021  [cited 19.04.2022]. Available from: https://www.awmf.org/uploads/tx_szleitlinien/025-014l_S1_Akute-lymphoblastische-Leukaemie-ALL-im-Kindesalter_2021-07.pdf.

                                        [5]     National Cancer Institute. Cancer Stat Facts: NHL — Diffuse Large B-Cell Lymphoma (DLBCL). 2019 [cited 19.04.2022]. Available from: https://seer.cancer.gov/statfacts/html/dlbcl.html.

                                        [6]     Lenz G., Chapuy B., Glaß B., Keil F., Klapper W., Nickelsen M., et al. Diffuses großzelliges B-Zell-Lymphom. 2021  [cited 19.04.2022]. Available from: https://www.onkopedia.com/de/onkopedia/guidelines/diffuses-grosszelliges-b-zell-lymphom/@@guideline/html/index.html#ID0ETHAE.

                                        [7]     Lees C., Keane C., Gandhi M. K. and Gunawardana J. Biology and therapy of primary mediastinal B-cell lymphoma: current status and future directions. British Journal of Haematology. 2019;185(1):25-41. DOI: https://doi.org/10.1111/bjh.15778.

                                        [8]     Orphanet. Primary mediastinal large B-cell lymphoma. [updated 20.04.2022; cited 20.04.2022]. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=98838.

                                        [9]     Sehic O. and Wild C. CAR-T Zell-Therapien in Entwicklung - Update 2022. Vienna: AIHTA, 2022  [cited 21.04.2022]. Available from: https://eprints.aihta.at/1368/1/Policy%20Brief_006a_1st%20Update.pdf.

                                        [10]   European Medicines Agency. Orphan Maintenance Assessment Report - Yescarta. London: Committee for Orphan Medicinal Products, 2018  [cited 19.04.2022]. Available from: https://www.ema.europa.eu/en/documents/orphan-maintenance-report/yescarta-orphan-maintenance-assessment-report-initial-authorisation_en.pdf.

                                        [11]   European Medicines Agency. Orphan Maintenance Assessment Report - Kymriah. London: European Medicines Agency, 2018  [cited 19.04.2022]. Available from: https://www.ema.europa.eu/en/documents/orphan-maintenance-report/kymriah-orphan-maintenance-assessment-report-initial-authorisation_en.pdf.

                                        [12]   National Cancer Institute. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. [updated 10.03.2022; cited 19.04.2022]. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.

                                        [13]   European Society for Blood and Marrow Transplantation. EBMT Annual Report 2021. [cited 21.04.2022]. Available from: https://www.ebmt.org/annual-report-2021.

                                        [14]   Ernst M., Oeser A., Besiroglu B., Caro-Valenzuela J., Abd El Aziz M., Monsef I., et al. Chimeric antigen receptor (CAR) T?cell therapy for people with relapsed or refractory diffuse large B?cell lymphoma. Cochrane Database of Systematic Reviews. 2021(9). DOI: 10.1002/14651858.CD013365.pub2.


                                        [1]https://www.awmf.org/uploads/tx_szleitlinien/025-014l_S1_Akute-lymphoblastische-Leukaemie-ALL-im-Kindesalter_2021-07.pdf

                                        [2]https://www.onkopedia.com/de/onkopedia/guidelines/diffuses-grosszelliges-b-zell-lymphom/@@guideline/html/index.html#ID0E3NAE

                                         

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