Introduction
Chimeric antigen receptor (CAR) T cell therapy, a novel type of treatment for hematological malignancies, utilizes genetically modified T cells expressing synthetic CARs that can subsequently trigger an immune response against cancer cells carrying a specific target surface protein [
1]. CAR T cell therapies are most advanced in B cell neoplasia, with licensed therapies directed against CD19 or B cell maturation antigen (BCMA) antigens in lymphoma, leukemia, or multiple myeloma indications respectively. When infused back into the patient, the CAR T cells bind the CD19 or BCMA antigens expressed in B cell-derived malignancies in a major histocompatibility complex (MHC)-independent manner, thus bypassing tumor-induced downregulation of the MHC complex [
2]. The CAR construct also contains a zeta chain of the T cell receptor (TCR) in combination with costimulatory molecules like IBB4 or CD28, which together stimulate a very strong immune response against CD19- or BCMA-positive cells [
2]. While the majority of CAR constructs today apply autologous T cells as a basis [
1], allogeneic CAR constructs are also in development [
3].
The first two CAR T cell therapies were approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2017/2018 for relapsed/refractory diffuse large B cell lymphoma (DLBCL) patients after two lines of systemic therapy (axicabtagene ciloleucel and tisagenlecleucel), for primary mediastinal large B cell lymphoma (PMBCL) after two lines of systemic therapy (axicabtagene ciloleucel), and for relapsed/refractory B cell acute lymphoblastic leukemia (ALL) in patients up to 25 years (tisagenlecleucel) [
4‐
7]. Since April 2022, in total six CAR T cell therapies have received regulatory approvals for different hematological malignancies, including DLBCL and PMBCL [
4‐
9], ALL [
5,
6,
10], mantle cell lymphoma (MCL) [
10,
11] follicular lymphoma (FL) [
4‐
7], and multiple myeloma [
12‐
14], and further indications are under investigation for CAR T cell therapies [
2]. The side effect profile of these CAR T cell therapies varies substantially according to the targeted antigens, the costimulatory molecules used and probably the type of malignant disease. Side effects comprise cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immunosuppression with infection [
15], which can be well handled in experienced CAR T centers.
DLBCL constitutes the largest indication among non-Hodgkin lymphomas globally with an estimated share of about 30–40% of cases [
16]. Relapsed or refractory DLBCL patients after two lines of systemic therapy have previously been characterized by very poor clinical outcomes with only limited therapeutic options [
17]. Recently, however, long-term CAR T cell therapy studies have demonstrated improved outcome, with 44% of DLBCL patients in third line surviving beyond 4 years after having received CAR T cell therapy [
18]. More recent studies also demonstrate promising results of CAR T cell therapies in DLBCL patients after first relapse in direct comparison with the current standard of care high-dose chemotherapy and autologous stem cell transplant [
19,
20], with one of these CAR T cell therapies having been approved by the FDA [
7].
In Austria, the first DLBCL patient received CAR T cell therapy within a clinical trial in the Vienna General Hospital AKH in 2016 [
21]. As of 2021, six CAR T centers are qualified/certified by an industry-driven process mandated by the EMA to perform licensed CAR T cell therapy for DLBCL patients (Vienna General Hospital AKH and St Anna Children Hospital Vienna, Paracelsus Medical University Salzburg/Salzburg Cancer Research Institute, Medical University Innsbruck, Medical University Graz, and Ordensklinikum Linz) and an additional one is planned in Lower Austria. Currently, five of nine Austrian federal provinces have a CAR T center [
21], whereas the provinces Burgenland, Kärnten and Vorarlberg rely on cross-province referral of DLBCL patients for CAR T cell therapy. Besides routine treatment, the centers also carry out research of CAR T cell therapies, with more than eight separate studies active or in the recruitment process in Austria in 2021 [
22‐
29]. The CAR T centers’ strong participation in CAR T cell therapy studies has helped to build deep expertise for this novel therapy in Austria already from an early stage.
The CAR T centers cooperate within a national CAR T network that focuses on coordinating the implementation of CAR T cell therapy in Austria [
30]. As part of this initiative, the members of the CAR T network specified quality requirements for CAR T centers, encompassing structural (e.g., hygiene, outpatient care), personnel as well as work-processes-related aspects [
31]. These are highly similar to the criteria defined by the Austrian Ministry of Health which together with the health platforms of the individual provinces is finally responsible for approving quality criteria for the remuneration of therapies. While the only listed contraindications in the summary of product characteristics (SmPC) for all approved CAR T therapies are hypersensitivity to the active substance or to any of the excipients or contraindications of the lymphodepleting chemotherapy [
4,
5,
8], the CAR T network also introduced a national CAR T algorithm for assessing eligibility of DLBCL patients for licensed CAR T cell therapies (Table
1; [
31]), with selection criteria closely matching the inclusion criteria used for the registrational clinical trials ZUMA‑1 and JULIET [
32,
33]. However, this algorithm is a recommendation only and according to Austrian law treatment decisions are made independently by the responsible physicians at the treating centers.
Table 1
Data points and patient numbers reflecting 2021 CAR T‑cell therapy access analysis for DLBCL patients in Austria. Comments/References list the source used to extract, calculate or estimate patient numbers based on previously published resources
Diffuse large B-cell lymphoma (DLBCL) incidence (2021) | 556 | |
Incidence estimation: 6.12/100,000, based on average of DLBCL population incidence estimation for Germany (4.91/100,000; Worldometers.info (n. d.); Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) [ 34]) and France (7.33/100,000; Worldometers.info (n. d.); Haute Autorité de Santé, [ 35]) |
DLBCL patients in first-line systemic therapy | 478 | 86% of DLBCL patients estimated to undergo first-line systemic therapy, based on estimation for France (Haute Autorité de Santé, [ 35]) |
DLBCL patients relapsed/refractory after first-line therapy | 172 | 31% of DLBCL patients estimated to be refractory or in relapse after first-line systemic therapy, based on estimation for Germany (IQWiG [ 34]) and France (Haute Autorité de Santé, [ 35]) |
DLBCL relapsed/refractory after second-line therapy (European medicine agency (EMA) DLBCL label indication for licensed chimeric antigen receptor (CAR) T products) | 89 | 16% of DLBCL patients estimated to be refractory or in relapse after second-line systemic therapy, based on estimation for Germany (IQWiG [ 34]) and France (Haute Autorité de Santé, [ 35]) |
This corresponds to the EMA DLBCL label indication for licensed CAR T products [ 4, 5] |
DLBCL patients eligible for licensed CAR T products under clinical trial criteria (Austrian CAR T algorithm) | 56 | 10% of DLBCL patients estimated to be eligible for CAR T cell therapy base on the registrational trial criteria, based on estimation for France (Haute Autorité de Santé, [ 35]) and the Netherlands, Austria, Spain [ 36] and Italy [ 37] |
The Austrian CAR T algorithm for selection of routine patients for CAR T cell therapy is considered to match the registrational trial criteria closely [ 31‐ 33] |
DLBCL patients eligible for licensed CAR T products and not selected for clinical trials | 51 | 9% of DLBCL patients eligible for licensed CAR T products under the Austrian CAR T algorithm are estimated to be selected for clinical trials |
CAR T therapy transfused patients | 19 | 19 patients meeting AT CAR T Network criteria are transfused with commercial CAR T treatment |
The key steps along the treatment sequences of a DLBCL patient in Austria from diagnosis to eventual CAR T cell therapy may be as follows: in most patients with DLBCL with the exception of primary central nervous system (CNS) lymphoma and without contraindications and/or special molecular findings, diagnosis will be followed by a risk-adapted, anthracycline-based rituximab-containing chemoimmunotherapy in first line [
38]. Due to the recent EMA approval of polatuzumab vedotin (Polivy) for treatment of newly diagnosed DLBCL patients on April 4, 2022 [
39] based on the POLRAIX data [
40], therapy in the frontline setting should be stratified based on age and/or the International Prognostic Index (IPI). Approximately 60% of patients will achieve a complete remission under R‑CHOP; however, about 30% of patients relapse and 10% of patients are primary refractory to first-line therapy [
41,
42]. Relapsed/refractory DLBCL patients are then usually treated with salvage therapy as well as subsequent autologous hematopoietic stem cell transplantation if possible [
38]. However less than 40% of relapsed/refractory patients will proceed to stem cell transplantation due to lack of response to salvage chemotherapy [
43]. Durable remissions with stem cell transplantation have been achieved in 31% of DLBCL patients in one series [
44] and 2‑year event-free survival was lower than 20% in another series [
43] highlighting a significant unmet need for effective therapeutic options. Patients with DLBCL who relapsed or were refractory after the two lines of therapy would become eligible for a CAR T cell therapy based on the EMA-approved indications [
4,
5,
8] and the Austrian CAR T algorithm criteria [
31]. In light of promising clinical results [
19,
20] and the recent approval of a CAR T cell therapy in primary refractory and relapsed DLBCL patients by the FDA [
7,
9], it is expected CAR T cell therapies will soon also be approved by the EMA for use after first relapse and Austrian hemato-oncologists are already entitled by legislation for off-label use to apply CAR T cell therapy in this indication.
The identification of DLBCL patients eligible for CAR T cell therapy should occur by the treating hemato-oncologist at an early stage due to an often very rapid progression of the disease. Confirmation of eligibility for CAR T cell therapy may happen directly within a CAR T cell center, particularly when these centers also regularly serve for first-line therapy for aggressive lymphomas or in a virtual regional tumor board in discussion with the referring hospital when treatment is more decentralized. The CAR T center then arranges the leukapheresis and the transfer of the patient’s cells to the pharmaceutical manufacturer for CAR T cell production. In most cases, patients will receive an individualized bridging chemo- or radiotherapy to limit disease progression followed by a lymphodepleting conditioning therapy to support CAR T cell expansion [
45,
46]. Patients are closely monitored to manage potential adverse events for as long as necessary due to the individual course, with regular follow-up visits at the CAR T center required after discharge. However, outpatient strategies are also under investigation [
47], which could reduce the requirement for a hospital stay by the patients after CAR T cell therapy.
Materials and methods
To analyze the CAR T cell therapy access situation in Austria and identify potential barriers for patients, a systematic analysis of the DLBCL patient numbers in 2021 along with the treatment sequence was conducted. The analysis covers a typical CAR T DLBCL patient treatment pathway in Austria, ranging from initial diagnosis to CAR T cell therapy. The critical parameters defining the treatment sequence include (i) DLBCL incidence, (ii) treatment success and numbers of patients requiring second- and third-line therapy, (iii) proportion of third-line DLBCL patients that are eligible for CAR T therapy based on the Austrian Algorithm criteria, (iv) numbers of third-line DLBCL CAR T eligible patients treated within clinical trials, and (v) numbers of third-line DLBCL CAR T eligible patients successfully infused with a licensed CAR T therapy in the routine setting.
Since at the time of writing both recent and specific public data on DLBCL incidence and treatment patterns were not available in Austria, published estimations from France [
35] and Germany [
34] were used to approximate the DLBCL incidence in Austria, as well as patient flow in first, second and third line. The proportion of CAR T eligible patients in Austria was estimated based on estimations for France [
35], the Netherlands, Austria, Spain, and Italy [
36,
37] as well as recent real-world analyses [
48‐
51]. Data on the use of CAR T cell therapies in Austria have been retrieved from recently published reports. In a recent manuscript by the European Society for Blood and Marrow Transplantation (EBMT), estimated data on CAR T use in 2019 in Austrian was presented [
52] Unfortunately, this publication does not define how these data were obtained and controlled for correct coverage. Furthermore, since the approved products received an EC marketing authorization by mid-August 2018, it is very likely that the reported numbers in 2019 reflect patients treated in both clinical trials and in the routine setting, since a considerable number of Austrian DLBCL patients during this time were treated with CAR Ts in clinical trials [
22‐
24,
26]. In a recently published analysis performed by the Austrian CAR T Network, retrospective data on patients receiving CAR T therapy in the routine setting have been presented [
53].
Details and results of the full analysis plan are available in Table
1.
Conflict of interest
G. Hopfinger: speakers’ bureau participation: Kite Pharma, Takeda, Roche, Celgene, GlaxoSmithKline, Gilead, Janssen, Novartis, Bristol Myers Squibb, BeiGene; honoraria: Kite Pharma, Takeda, Roche, Celgene, GlaxoSmithKline, Gilead, Janssen, Novartis, Bristol Myers Squibb, BeiGene; travel support: Roche, Jannssen. B. Rupp: honoraria from: Gilead; consultancy or advisory role for: Gilead. R. Greil: honoraria from Gilead, Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, Sanofi; consultancy or advisory role for Gilead, Celgene, Novartis, Roche, BMS, Takeda, Abbvie, AstraZeneca, Janssen, MSD, Merck, Daiichi Sankyo, Sanofi; research funding: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo; travel, accommodations, expenses: Roche, Amgen, Janssen, AstraZeneca, Novartis, MSD, Celgene, Gilead, BMS, Abbvie, Daiichi Sankyo.
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