Blood cancers

CAR T-cell therapy in DLBCL: patient selection, referral and predictive markers


“If there’s one thing I’d like clinicians to remember, it’s not to hold back on sending through a referral for consideration of your patient with diffuse large B-cell lymphoma (DLBCL) for CAR T-cell therapy,” says Dr Jason Butler, a clinical haematologist at the bone marrow transplant unit at the Royal Brisbane and Women’s Hospital which assesses and treats patients with DLBCL with CAR T-cell therapy. In a follow-up to the CAR-T Connect medical education event hosted by Novartis in August, the limbic spoke with Dr Butler about the delivery of CAR T-cell therapy in Australia. It turns out that understanding who is, and who is not, suitable for treatment may be simpler for referring physicians than we realise.

A reminder on CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy is a novel reprogramming approach to cancer therapy. It involves the genetic modification of a patient’s T-cells to express a synthetic CAR that redirects the T-cell to recognise tumour antigens. CAR T-cell therapy has been a popular area of study for B cell malignancies, particularly as they express specific molecules (such as CD19 for example), which are not expressed on other tissues.1 The process involves T cells to be harvested from the blood, then genetically modified to express the CAR, then re-infused into the patient.1 This process can take several weeks, Dr Butler explained. Once back in the body, in general there is a peak and expansion that occurs around 1-2 weeks after infusion, followed by a slow decline that can last weeks to years.2 In the weeks following infusion, patients are monitored for side effects, notably cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome.3 CAR T-cell therapy immune-mediated adverse events have the potential to impact any organ system,3 which is why overall fitness plays into treatment decisions.

Stable disease and fitness of the patient are key criteria for treatment selection

Dr Butler explained that in Australia, the expectation of patients to be treated with CAR T-cell therapy is in the vicinity of around 250 nationally, per year. The key decision lies in who is actually fit enough to receive treatment and how stable their disease is. He explained, “with a treatment like CAR T-cell therapy, you’re looking at quite an advanced and personalised approach to treatment, which comes at a cost. Because there is a delay between cell collection and receipt of the manufactured product, you need to ensure that the patient’s disease is stable enough to bridge that gap and the patient needs to be fit enough to undergo the entire process as well. It’s really those two things that drive appropriate patient selection. By fitness we mean their performance status, as well as underlying organ function and by disease stability we mean the patient’s disease is at a tempo that will allow them to wait out the manufacturing process. While we can give some bridging treatment, around 20% of patients aren’t able to control disease for that time.”

The patient eligibility criteria for CAR T-cell therapy in DLBCL in Australia is currently:

Patients with DLBCL who:4

  • Have relapsed after autologous stem cell transplantation; or
  • Have relapsed after, or are refractory to, at least two prior systemic therapies

AND

  • Patient must have a World Health Organization (WHO) performance status of 0 or 1

AND

  • Patient must have sufficient organ function, including:
    • Renal function
    • Cardiac function
    • Pulmonary function

AND

  • Patient must not have uncontrolled infection, including uncontrolled human immunodeficiency virus (HIV) or active hepatitis B or C infection

AND

  • Patient must not have primary CNS lymphoma

AND

  • Patient must not have uncontrolled secondary central nervous system (CNS) disease, or secondary CNS disease anticipated to be uncontrolled at the time of lymphocyte infusion

AND

  • The treatment team must consider the patient’s condition can be effectively managed during lymphocyte collection and manufacturing, to allow for the absence of rapidly progressive disease at the time of lymphocyte infusion.

There’s a national team of experts ready to assess patients

Dr Butler explained how close the CAR T-cell medical faculty is in Australia. “We hold national meetings and talk about the patient cases and share knowledge so that we may benefit from the collective knowledge gained. Right now, around 80% of patients referred are considered eligible to proceed. The key of course is having patients referred early enough to meet the fitness and stable disease criteria. It’s really not a hassle for us to undertake the patient assessment. We’d rather have you refer the patient early if you were unsure than wait until their disease progresses and they do not meet criteria for treatment.”

A national approach to treatment also has its benefits in terms of access for those patients who may be borderline in their State. “For example,” Dr Butler explained, “our centre has determined an age limit of 75 years as we are a new centre, just starting out. Based on the variability of experience and volume of patients across the country, we may be able to refer a patient to another centre where an age of 75 years alone does not disqualify them from their program. As the collective experience grows I expect the criteria to be refined, when we’re confident we’ll be able to get those patients through to infusion.”

How do you connect with your local service?

In Queensland, Dr Butler noted that major haematology facilities were made aware of the referral pathway via an email from the clinic. “I’d say most people connected with the major facilities would be aware of how to access the service, but perhaps some in private practice may have had limited contact with us up to now. We are looking at doing some CAR T-cell therapy education where experts provide 15-minute virtual in-services facilities about how the process works, how to refer and what information we need when you refer a patient. Aside from that, Dr Butler encourages clinicians to check in with the Peter Mac Centre and Lymphoma Australia for some good resources for both clinicians and patients.

 References:

  1. Srivastava S, Riddell SR. J Immunol 2018;200(2):459-468.
  2. Chavez JC, et al. Ther Adv Hematol 2019;10:2040620719841581.
  3. Wudhikam K, et al. Blood Adv 2020;4(13):3024-3033.
  4. Public Summary Document. Available at: http://www.msac.gov.au/internet/msac/publishing.nsf/Content/A2B10F9A03293BC8CA2583CF001C7A4D/$File/1519.1%20Final%20updated%20PSD%20Nov%2019_redacted.pdf (accessed 18 September 2020).

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