Progress and challenges in B-cell lymphoma

The Haematology Association of Ireland Annual Meeting 2022 heard a lecture delivered by Prof John Leonard, Senior Associate Dean for Innovation and Initiatives at Weill Cornell Medicine, New York Presbyterian Hospital in the US, who delivered a State-of-the-Art lecture titled ‘Progress and challenges in precision therapy for diffuse large B-cell lymphoma’.

In his talk, introduced by Dr Amjad Hayat, Prof Leonard gave an overview of lymphomas and the standard treatment algorithm for the condition. He also presented a round-up of clinical trial data and discussed some of the potential challenges in practising precision medicine. “Sub-setting groups of patients has been very exciting and has a very strong scientific rationale, but unfortunately that has not really translated to the clinic,” said Prof Leonard.

“Now, in parallel, we have returned to strategies that are independent of the cell of origin. One example of what has changed things for the better in diffuse large B-cell lymphoma is CAR T-cell therapy, and you are all familiar with this… this immune effect has great potential for patients with relapsed large B-cell lymphoma. We now have several different CD19-directed CAR T-cell products in diffuse large B-cell lymphoma; they have some differences, but I would argue that they are more similar than they are different. All of these have significant activity in patients with recurrent diffuse large B-cell lymphoma… the response rates are fairly high, and the durability seems to be in patients with recurrent diffuse large B-cell lymphoma. If you get a response, particularly if you get a complete response, you have a good chance of achieving a longer-term remission, and potentially a cure.”

Prof Leonard presented trial data on CAR T-cell therapies and gave the attendees his key takeaway message on precision medicine strategies. “This is an agnostic therapy for cell of origin,” he told the conference. “As far as we know right now, there is not really a subset of patients that does better or worse with CAR T-cells. There are hints, if you look at hundreds of patients… to my mind, much of it, when we talk about the disease itself, it’s a case of ‘if you have better disease, you do better’.”

He briefly discussed other agnostic cell of origin therapies and offered his thoughts on how to make precision medicine strategies more effective. “Patient selection in clinical trials has resulted in, or contributed to, the fact that precision medicine strategies have failed,” said Prof Leonard. He also referenced a study by himself and colleagues published in 2017 to show the limitations of clinical trials in this area. 

“So, are we ready for precision therapy in diffuse large B-cell lymphoma?” Prof Leonard concluded. “We have lots of biomarkers that seem to predict outcomes; we have lots of active drugs that seem to be appropriate for subsets. However, these subsets seem to be getting more and more sub-classified, so that’s making it harder. Patient selection – whether we are doing it on purpose or that’s just the way it’s working out – may be an issue in operationalising that, because if you are targeting a less favourable subset, and you are excluding all the less-favourable patients, how are you going to see if your drug makes a difference?

“In parallel, all of these impactful drugs are working, but they are agnostic of subset, and that just tells us that they are imparting immune-based therapies and the immune system may or may not be as related to these subsets of disease. So why is this challenging?” he continued. “It may be challenging because we don’t have the best drugs; it may be challenging because we don’t have an assay that works, and that assay has to be robust and put patients in different subsets, and it has to be fast enough that you can act on it, but patient selection is a big factor in all of this.

“So as we go forward, we need to continue to use control groups, because when we make these retrospective-prospective comparisons, it’s going to make it challenging to interpret. We need better drugs, better biomarker assays, and we need flexibility, particularly in the first cycle, so that we can get more patients on the study, and innovative study design could sort all of this out.”