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My paper of the month - Consequences of increasing waiting times for treatment with commercially available autologous CAR-T cells targeting CD19 on the one-year all cause- survival for patients with relapsed/ refractory diffuse large B cell lymphoma.

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Each month one member of the EBMT Scientific Council will select and comment a recent paper in the field of stem cell transplantation and cellular therapy that was published in high ranked journals.

For this month Newsletter, Christian Chabannon, Chair of the Cellular Therapy & Immunobiology Working Party, comments on the publication entitled “Impact of increasing wait times on overall mortality of chimeric antigen receptor T-Cell Therapy in large B-Cell lymphoma: a discrete event simulation model" published in JCO Clinical Cancer Informatics.

Consequences of increasing waiting times for treatment with commercially available autologous CAR-T cells targeting CD19 on the one-year all cause- survival for patients with relapsed/ refractory diffuse large B cell lymphoma.

Authors: Stephen Tully, Zeny Feng, Kelly Grindrod, Tom McFarlane, Kelvin K.W. Chan and William W.L. Wong

Autologous lymphocytes that are genetically engineered to express a Chimeric Antigen Receptor (CAR) or CAR-T Cells represent a promising therapy for patients with hematologic malignancies and potentially solid tumors (1). Currently, two gene therapy medicinal products (GTMP) have been approved by the US FDA, EMA, and several other health agencies worldwide; both are autologous and express a CAR targeting the pan-B membrane antigen CD19: tisagenlecleucel (Kymriah®, Novartis) is approved for the treatment of relapsed / refractory pediatric and adult (<= 25 years old) Acute Lymphoblastic Leukemia (ALL) (2) and relapsed / refractory diffuse large B cell non-Hodgkin’s lymphoma (DLBCL) (3); axicabtagene ciloleucel (Yescarta®, Kite/Gilead) is approved for relapsed / refractory DLBCL and primary mediastinal B-cell non-Hodgkin’s lymphoma (NHL) (4). Additional products are expected to be approved in the near future, either for NHL, or for multiple myeloma (CAR-T Cells targeting the B-Cell Maturation Antigen, BCMA) (5-7). These GTMP are manufactured on demand, from autologous blood mononuclear cells collected by apheresis, and by central manufacturing organizations (CMO) that are geographically distant from the treating hospital; the turnaround time to GTMP availability depends on a number of factors including slot availability at the local apheresis facility, slot availability at the CMO, length of the manufacturing process and delay in obtaining the results of final biological controls on the GTMP that are mandatory for product release by the qualified pharmacist, and the time needed to ship the starting material from the local site to the CMO and back from the CMO to the treating hospital; the turnaround time is typically in the range of 3 to 6 weeks, depending on hospital location and organization, and with currently available manufacturing facilities and processes. In addition, the safety profile of this new class of innovative therapeutics requires a specific hospital organization needed to properly care for high-grade side-effects such as Cytokine Release Syndrome (CRS) or Immune effector Cells Associated Neurotoxicity Syndrome (ICANS) that occur in a significant fraction of treated patients (8). To offer access to CAR-T cells, hospitals must be qualified by the Manufacturing Authorization Holder (MAH), a requirement included in the approval granted by the US FDA and by EMA, and in some countries by their health authorities. As a consequence, the number of medical centers offering treatment with CAR-T cells currently represents only a fraction of general of specialized hospitals that treat patients with hematological malignancies (9); many patients must be referred to a distant medical center, and solve the logistical issues for themselves and their families. Finally, conditions for reimbursement of these costly GTMP and the associated care provided by hospitals vary from country to country, and the organization of some healthcare systems may produce counter incentives for hospitals. All of these elements contribute to potential delays in patients receiving these potentially lifesaving therapies. Although extended follow-up of patients included in registration studies provide reassuring data (10), it is noteworthy that Health Technology Assessment (HTA) agencies from many countries are interested in measuring the medical value and the cost-effectiveness (11) of these costly GTMP in real life conditions, and insist on evaluating clinical results in an intent-to treat (ITT) approach: this justifies that patients be registered not when they received treatment with CAR-T Cells, but as soon as a multidisciplinary medical team has positively decided on treatment and the GTMP is ordered by the hospital pharmacy from the MAH.

In their recently published report (12), Tully et al examine the consequences of increasing wait times on the outcome of patients with relapsed/refractory DLBCL – the most common CAR-T Cell indication at the moment - that are candidates for treatment with tisagenlecleucel or axicabtagene ciloleucel. Using a simulation model and published data, they examined the consequences of incremental wait times – from one to 9 months - on one-year all-cause mortality. The authors demonstrate that the predicted one-year mortality can be increased by more than two fold. Interestingly, even a modest delay – 1 or 2 months - in bringing CAR-T Cell to the patient significantly increases the one-year mortality, both for axicabtagene ciloleucel and with tisagenlecleucel, whether or not a bridging chemotherapy is administered during the turnaround time. Depending on the expected wait time, administering current standard- of-care for these patients, i.e. salvage chemotherapy may turn out to be more beneficial that treatment with CAR-T Cells.

Although the authors recognize methodological limitations in their simulations - there exists no head-to head comparison of the two approved products, nor direct comparison to salvage chemotherapy - these important data reinforce the needs to further improve access to these innovative treatments. This can only be done in the context of a multi-stakeholders effort, including competent authorities, healthcare payers, healthcare providers and pharmaceutical companies, all of them aided by patients and patients’ advocates. The results of this analysis are only valid for a limited period of times, as the number of CMOs augment, or manufacturing processes are improved thus decreasing the rate of manufacturing failures; however, some organizational hurdles in the healthcare system may be more difficult to tackle than purely technical issues, and will need prolonged efforts in order to bring optimal benefits to the patient community while optimizing the use of healthcare resources.
 

1. June CH, O'Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359(6382):1361-5.
2. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439-48.
3. Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017;377(26):2545-54.
4. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531-44.
5.  Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2019;380(18):1726-37.
6. Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210-21.
7.  Zhao WH, Liu J, Wang BY, Chen YX, Cao XM, Yang Y, et al. A phase 1, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapsed or refractory multiple myeloma. J Hematol Oncol. 2018;11(1):141.
8.  Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F, et al. Management of adults and children undergoing CAR t-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2019.
9. Bach PB. National Coverage Analysis of CAR-T Therapies - Policy, Evidence, and Payment. N Engl J Med. 2018;379(15):1396-8.
10. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42.
11. Lin JK, Muffly LS, Spinner MA, Barnes JI, Owens DK, Goldhaber-Fiebert JD. Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma. J Clin Oncol. 2019;37(24):2105-19.
12. Tully S, Feng Z, Grindrod K, McFarlane T, Chan KKW, Wong WWL. Impact of Increasing Wait Times on Overall Mortality of Chimeric Antigen Receptor T-Cell Therapy in Large B-Cell Lymphoma: A Discrete Event Simulation Model. JCO Clin Cancer Inform. 2019;3:1-9.