CAR T Cell Therapy Should Proceed During the COVID-19 Pandemic

Share

By Parastoo B. Dahi, MD Miguel-Angel Perales, MD

CAR T cells attacking cancer

Treatment with chimeric antigen receptor T cell therapy should proceed in patients with B cell non-Hodgkin lymphomas and B cell acute lymphocytic leukemia, despite the challenges of Covid-19, according to the CAR T Cell Consortium, a collaboration of investigators from eight U.S. academic institutions.

Administering CAR T cell therapy during a pandemic requires extensive discussion of the risks and benefits, as well as careful assessment, planning, and utilization of resources. Together with our colleagues in the CAR T Cell Consortium, we reviewed the current questions and concerns and developed consensus recommendations for enhancing patient survival and quality of life.

In the paper, published April 14, 2020, in the journal Biology of Blood and Marrow Transplantation, the CAR T Cell Consortium outlines consensus recommendations for treatment centers in the format of answers to seven key questions.

It is essential to anticipate resource challenges because CAR T cell therapy cannot be aborted once it is initiated.
Parastoo B. Dahi Associate Attending Physician

What resources are required for the safe administration of CAR T cell therapy during the COVID-19 pandemic?

It is essential to anticipate resource challenges because CAR T cell therapy cannot be aborted once it is initiated. Treatment centers may be affected at different times based on their location and local supply chain issues.

Practical considerations for safely treating patients in light of potential disruptions include:

  • Establish a triage algorithm to safely delay or cancel as many CAR T activities as possible.
  • Ensure dedicated staff are available for product receipt, processing, and infusion.
  • Prioritize products that can be given on an outpatient basis and ensure appropriate follow-up to evaluate patients who experience toxicity.
  • Initiate lymphodepleting chemotherapy only after receipt of the cell product.
  • Encourage virtual team rounds and perform only one exam per patient per day, if appropriate. Consider forgoing exams that will likely not inform assessment or management.
  • Ensure patients have a housing plan in place for the four weeks surrounding their procedure.
  • Perform outpatient visits via telemedicine, when feasible.
  • Minimize all non-essential lab work and radiology appointments.
  • Preferentially use oral over parenteral medications, when appropriate.
  • Ensure a cell therapy team member is always available to respond to COVID-19 issues and establish a workflow for COVID-19-positive patients. Consider establishing specific inpatient units for COVID-19 patients with dedicated rounding teams.
Back to top

Should the current COVID-19 pandemic determine cellular therapy utilization?

Centers should continue to offer CAR T cell therapies for patients with refractory diffuse large cell lymphoma (DLBCL) and ALL, using appropriate patient selection criteria and strict infection control precautions.

CAR T cells are potentially curative for these patients who otherwise would have a dismal prognosis.(1),(2),(3),(4) The therapy has significantly improved complete response rates to about 40 to 54 percent in DLBCL and 81 percent in ALL. Most remissions are free from minimal residual disease. They are sustained without further interventions, with a median follow-up exceeding two years and as long as six years in many cases. Since follow-up is so long, and most relapses occur by six to 12 months,(5),(6),(7) we believe the treatment has saved the lives of many patients with highly refractory cancers.

We recommend that institutions develop strategic triage algorithms to ensure continued delivery of life-saving treatments while weighing institutional resources and needs. Patients should be managed as much as possible in outpatient settings to preserve inpatient resources.

Other considerations include early intervention to address cytokine release syndrome (CRS) and neurotoxicity as well as preemptive strategies to prevent infection.

Significant toxicities, including cytopenia, CRS, and neurotoxicity may occur with CAR T cell therapy.(5),(6),(7),(8),(9) A prolonged inability to mount antibody responses is particularly concerning during the COVID-19 pandemic,(10),(11),(12) especially as many CAR T cell recipients are inpatients with a frequent need for ICU care. (8)

For clinical trials, we recommend placing the following on hold: phase I trials designed primarily to demonstrate safety, studies investigating CAR T cells as first-line therapy, and phase III studies comparing CAR T versus standard of care, such as autologous stem cell transplantation. Trials that should continue are phase II trials, and studies aimed at mitigating CRS and preventing neurotoxicity.

Back to top

How do you approach patient selection for cellular therapy in relapsed/refractory aggressive B cell non-Hodgkin lymphoma in the era of COVID-19?

During the pandemic, it is essential to determine criteria for selecting patients who may achieve meaningful remission as well as those who have a lower risk of toxicity and therefore require minimal use of resources.

We recommend that all relapsed/refractory DLBCL patients with preserved performance status (Eastern Cooperative Oncology Group (ECOG) ≤ 2), limited comorbidities (cardiac, renal, hepatic, and bone marrow reserve) and tumor kinetics that can afford the time to undergo leukapheresis and CAR T cell manufacturing, be considered for treatment.

Studies show that elderly patients can fare as well as younger patients,(13),(14) especially when functional status and comorbidities are carefully considered. These considerations are critical during the COVID-19 pandemic as older adults have a significantly higher risk of severe illness if they become infected with SARS-CoV-2.

Note that tumor bulk has not been consistently associated with poor efficacy among recipients of commercial CAR T cell products, but it has been associated with higher rates of acute toxicity.(13),(15),(16) Performance status (ECOG >2) and elevated serum lactate dehydrogenase can be used as surrogate indicators of rapid tumor growth and identify patients at high risk of CAR T cell failure. We recommend delaying CAR T cell therapy for these patients.

Back to top

How do you approach patient selection for cellular therapy in relapsed/refractory ALL in the era of COVID-19?

For centers able to access tisagenlecleucel (tisa-cel), which is approved for patients with relapsed/refractory ALL up to the ages of 25 years, we recommend proceeding with treatment.

Note that in ALL, patient selection based on disease burden is not practical: the disease burden that is most predictive of CRS is measured at the end of lymphodepleting chemotherapy, (7) at which point, patients immediately receive the CAR T cell infusion.

Although rates of CRS are higher in ALL compared with DLBCL,(6),(7) recent analyses showed that ICU admission rates dropped from 40 percent to 13 percent over a four-year period. Also, grade 3 and 4 CRS rates for the commercial product have dropped to about 14 percent recently, (17) down from 48 percent seen in the ELIANA registration trial for tisa-cel. A recent prospective trial of preemptive administration of tocilizumab met its primary endpoint of showing a one-third reduction in grade 4 CRS among patients with a high disease burden. (18)

Back to top

How do certified treatment centers support cellular therapy patients during the COVID-19 pandemic?

The COVID-19 pandemic has placed massive constraints on the delivery of cellular therapy, including partial closures of outpatient clinics, decreased capacity in infusion suites, fewer clinical staff, and closures or reductions in outpatient housing resources. Therefore, CAR T cell therapy should be provided on an outpatient basis, wherever feasible, to reduce strain on inpatient resources. (19)

Treatment should be coordinated with infectious disease experts and based on guidelines from the Centers for Disease Control and Prevention and The American Society for Transplantation and Cellular Therapy (ASTCT), which has issued interim guidelines for managing COVID-19 issues in cellular therapy and stem cell transplantation recipients. (20)

There are no proven therapies available at present for treating immunocompromised patients with COVID-19. We encourage centers to work with their infectious disease and pulmonary colleagues to ensure that cell therapy patients are not excluded from clinical trials enrolling COVID-19-positive patients.

Steroids should be used judiciously for managing CRS and neurotoxicity syndrome in COVID-19-positive patients, given that their long-term use is associated with detrimental effects.(21),(22),(23) CAR T cell patients are severely immunocompromised due to heavy pretreatment, lymphodepleting chemotherapy, neutropenia, hypogammaglobulinemia, and the use of steroids to treat toxicities associated with CAR T cell therapies. We recommend continuing supportive care measures, such as the use of granulocyte-colony stimulating factor for prolonged neutropenia, together with standard antiviral, antifungal, and antimicrobial prophylaxis.

For guidance on specific measures to mitigate the risk of COVID-19 and its complications before and after treating patients with CAR T cell therapy, please refer to Table 2 in the paper.

Back to top

How do you use and prioritize tocilizumab in the era of COVID-19?

Tocilizumab, a recombinant monoclonal antibody to the IL-6 receptor, is the mainstay in managing patients with advanced CRS after CAR T cell therapy.(24),(25),(26),(27) The FDA approval was based on retrospective data that showed a majority of patients with severe or life-threatening CRS responded to one or two doses. (28) Since then, its use has shifted toward earlier intervention given data that showed a decrease in the severity of CRS without a reduction in CAR T cell efficacy.(25),(26),(27),(29)

There are a growing number of anecdotal accounts of the drug reducing the severity and duration of COVID-19 symptoms and allowing for weaning from supportive ventilation. (30) This has led to off-label use of tocilizumab in symptomatic COVID-19 patients and the initiation of clinical trials, raising concerns about supplies becoming limited and rationing among patients with COVID-19 and those with FDA-approved indications.

We recommend centers continue to follow the Risk Evaluation and Mitigation Strategy guidelines on the package insert and have at least two doses of tocilizumab available for each patient before administering the CAR T cell infusion. We recommend early administration at the onset of grade 2 CRS and using no more than two doses per patient.

Back to top

How can certified treatment centers collaborate with referring oncologists to facilitate care in the era of COVID-19?

During the pandemic, patients presenting with relapsed/refractory DLBCL and ALL may have more advanced or symptomatic disease in light of deferred procedures and surveillance imaging due to social distancing measures.

Maintaining open lines of communication between referring community oncologists and treatment centers is critical. We recommend using telemedicine to speed consultations and limit unnecessary travel for patients who are obviously ineligible or inappropriate for CAR T cell therapy.

Problems can be minimized by providing referring providers with a detailed treatment plan, highlighting the duration of care at the treatment center and expected transition date back to community care. To comply with travel restrictions during the pandemic, we recommend limiting in-person visits to centers and forgoing routine surveillance in patients in complete remission and without risk of relapse, as appropriate.

Treating clinicians should provide patients with supporting documentation to allow them to avoid work and school obligations while the risk of COVID-19 transmission continues since as many as 61 percent of CAR T cell therapy recipients experience late infections. (31)

CAR T cell recipients with confirmed SARS-CoV-2 infection should be managed locally, if safe and feasible, to avoid overburdening treatment centers and to limit viral spread.

Back to top

Advancing Cancer Care During the COVID-19 Pandemic

At MSK, the health and safety our patients and staff is our top priority. Our researchers and clinicians are an important part of the international response to the COVID-19 pandemic. We continue to collaborate to deliver excellent, evidence-based care for our patients.

We are offering a twice-weekly scientific seminar series, MSK Science Spotlight, featuring lectures by leaders in basic and translational biomedical science. Seminars are available via livestream every Monday and Wednesday at ET. Seminars last 60 minutes, including 15 minutes for Q & A. No registration is required. Check out the schedule or watch past seminars here.

Dr. Dahi serves on the advisory board for Kite Pharma/Gilead. Dr. Perales has received honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda. He also serves on data safety and monitoring boards for Servier and Medigene, on scientific advisory boards of MolMed and NexImmune, and has received research support for clinical trials from Incyte, Kite Pharma/Gilead, Miltenyi Biotec, and Novartis.

Refer a Patient
Call our dedicated clinician access number at 646-677-7440 or click the link below, and one of our care advisors will assist you with your referral needs.
Refer Online
Back to top
  1. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–1808.
  2. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 851 2993 study. Blood. 2007;109:944–950.
  3. Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21:1907–1914.
  4. Gökbuget N, Dombret H, Ribera JM, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101:1524–1533.
  5. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T- cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–2544.
  6. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56.
  7. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–448.
  8. Riedell PA, Walling C, Nastoupil LJ, et al. A multicenter retrospective analysis of outcomes and toxicities with commercial axicabtagene ciloleucel and tisagenlecleucel for relapsed/refractory aggressive B-cell lymphomas. Biol Blood Marrow Transplant. 2020;26(suppl):S41–S42.
  9. Bachanova V, Perales MA, Abramson JS. Modern management of relapsed and refractory aggressive B-cell lymphoma: a perspective on the current treatment landscape and patient selection for CART-cell therapy. Blood Rev. 2020;40:100640.
  10. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–1517.
  11. Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018;131:121–130.
  12. Bhoj VG, Arhontoulis D, Wertheim G, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016;128:360–370.
  13. Nastoupil LJ, Jain MD, Spiegel JY, et al. Axicabtagene ciloleucel (axi-cel) CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: real world experience. Blood. 2018;132(suppl 862 1):91.
  14. Sano O, Nastoupil LJ, Fowler NHJ, et al. Safety of axicabtagene ciloleucel CD19 CAR T-cell therapy in elderly patients with relapsed or refractory large B-cell lymphoma. Blood. 2018;132(suppl 1):96.
  15. Neelapu SS, Ghobadi A, Jacobson CA, et al. 2-Year follow-up and high-risk subset analysis of Zuma-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients with refractory large B cell lymphoma. Blood. 2018;132(suppl 1):2967.
  16. Maziarz RT, Schuster SJ, Ericson SG, et al. Cytokine release syndrome and neurotoxicity by baseline tumor burden in adults with relapsed or  refractory diffuse large B cell lymphoma treated with tisagenlecleucel. Hematol Oncol. 2019;37:307.
  17. Grupp S, Hu ZH, Zhang Y, et al. Tisagenlecleucel chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory children and young adults with acute lymphoblastic leukemia (ALL): real world experience from the Center for International Blood and Marrow Transplant Research (CIBMTR) and cellular therapy (CT) registry. Blood. 2019;134(suppl 1):2619.
  18. Myers RM, Kadauke S, Li Y, et al. Risk-adapted preemptive tocilizumab decreases severe cytokine release syndrome (CRS) after CTL019 CD19-targeted chimeric antigen receptor (CAR) T-cell therapy for pediatric B-cell acute lymphoblastic leukemia (B-ALL). Biol Blood Marrow Transplant. 2020;26(suppl):S39.
  19. Dwivedy Nasta S, Namoglu EC, Hughes ME, et al. Hospitalization patterns with commercial CAR T-cell therapy: a single institution experience. Blood. 2019;134(suppl 1):3240.
  20. Waghmare A, on behalf of the American Society of Transplantation and Cellular Therapy Infectious Diseases Special Interest Group. Interim guidelines for COVID-19 management in hematopoietic cell transplant and cellular therapy patients, version 1.2. 2020.
  21. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam JS, Lim WS. Effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis. J Infect Dis. 2015;212:183–194.
  22. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395:473–475.
  23. Shang L, Zhao J, Hu Y, Du R, Cao B. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet. 2020;395:683–684.
  24. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–195.
  25. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47–62.
  26. Mahadeo KM, Khazal SJ, Abdel-Azim H, et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat Rev Clin Oncol. 2019;16:45–63.
  27. Yakoub-Agha I, Chabannon C, Bader P, et al. Management of adults and children undergoing chimeric antigen receptor 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. 2020;105:297–316.
  28. Le RQ,Li L,Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23:943–947.
  29. Gardner RA, Ceppi F, Rivers J, et al. Preemptive mitigation of CD19 CAR T- cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134:2149–2158.
  30. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. 2020. ChinaXiv. 202003.200026.
  31. Cordeiro A, Bezerra ED, Hirayama AV, et al. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biol Blood Marrow Transplant. 2020;26:26–33.