Professor Constantine (Con) Tam is a Melbourne-based expert in CLL and low-grade lymphoma whose sights are focused on curing these blood cancers. He is Clinical Lead for CLL and Low-Grade Lymphoma at Peter MacCallum Cancer Centre/Royal Melbourne Hospital and Professor of Haematology at the University of Melbourne where he teaches and supervises PhD students. Prof. Tam is the global lead for the novel BTK inhibitor, zanubrutinib, and he completed the world’s first study combining ibrutinib and venetoclax. Born in Hong Kong, he came to Australia as an 11-year-old and after completing his undergraduate degree, trained in medicine and haematology and worked at St Vincent’s, Peter Mac and Alfred hospitals before heading overseas for a two-year CLL fellowship at the MD Anderson Cancer Center in Texas (U.S.).

The latest news on CLL research are the small molecules–the BTK and BCL-2 inhibitors–and there’s a resurgence of interest in CAR T-cell therapy in CLL, says Prof. Con Tam.

“There are now many studies to show that we can combine BTK and BCL-2 [inhibitors], and those combinations are tolerable and get very deep responses,” he said.

“The most recent clinical trials have shown that these drugs, as either monotherapy or in combination with an antibody, are better than standard chemotherapy.

“But I think the next generation of trials will look at whether the combinations of both a BCL-2 and a BTK inhibitor will be even better than single agents.”

He is referring to ibrutinib (Imbruvica®) and the newer generation BTK inhibitors, zanubrutinib (BGB-3111) and acalabarutinib (Calquence®), which have all been studied in combination with the BCL-2 inhibitor, venetoclax (Venclexta®).

“Adding venetoclax to the regimen gives the advantage of patients potentially being able to come off these drugs.

“At the moment, you go on the BTK inhibitor and you’re pretty much stuck on it forever, because you never clear minimal residual disease (MRD),” explained Dr Tam.

“Whereas in combination with venetoclax, it seems most people can be cleared of MRD and can potentially stop taking both drugs; take a drug holiday.

“That’s quite an exciting prospect… being able to take tablets for a fixed duration–12 to 24 months of therapy–that will clear MRD. Then, just like after having chemotherapy, having a break.

“And CLL being CLL, we anticipate that the majority will eventually relapse and will be retreated. Hopefully, it will be years before that will happen.”

CAR T-cell therapy for CLL

Dr Tam said, “the other exciting thing” is the resurgence now of interest in CAR T-cells in CLL”.

CLL was one of the first diseases to respond to CAR T-cells in early trials.

“The first major report from the University of Pennsylvania was in fact in CLL, where three patients were successfully treated with CAR T-cells, and to my knowledge they remain cured.

“The attention has shifted since then to diffuse large B-cell lymphoma [DLBCL] and ALL [acute lymphoblastic leukaemia] because they’re more urgent diseases.”

Another reason is that in CLL patients, the quality of the CAR T-cells is not as good as in DLBCL and ALL patients, due to both the CLL itself and the cumulative effects of previous therapy.

“Often the CAR T-cells don’t work as well in CLL because the T-cells are less fit,” explained Dr Tam.

Ibrutinib has been used to improve the quality of the T-cells before they are collected for CAR T-cell therapy, and Dr Tam said it was time CAR T-cell therapy was used “in a more intelligent manner” to treat CLL; not as a “Hail Mary manoeuvre” when all other treatment options had stopped working and when a patient had a lot of CLL onboard.

“Under those circumstances, CAR T-cells are probably not expected to work well,” he said.

But if, for example, for patients in stable remission on ibrutinib, the T-cells are a lot more fit and there is a lot less CLL onboard to be treated, and CAR-T cells may be applied as a ‘curative’ procedure to achieve MRD clearance and terminate the need for indefinite ibrutinib therapy.

“You might be able to provide someone with a permanent cure to consolidate a good response to some other therapy,” said Dr Tam.

In other words, use CAR T-cell therapy more effectively by using it as an earlier line of treatment.

“If trials, like the one Deb’s [Deborah Henderson] on are able to show that people can get off indefinite ibrutinib therapy with CAR T-cells, then this might be quite worthwhile because CAR T-cells are expensive–$500,000 for the procedure–but that’s only about three years’ of having ibrutinib, in terms of costs,” said Dr Tam.

“And if you can have CAR T-cells, and no longer need ibrutinib, you are saving money in the long-term for the government.

“Also, ibrutinib doesn’t last forever, so you are circumventing the problem of future ibrutinib resistance and the side effects that may be associated with ibrutinib.

“These drugs are so expensive. CAR T-cell therapy is an expensive procedure and so are the drugs CLL patients are on [like ibrutinib and venetoclax].

“It may work out that this [CAR T-cell therapy] is a worthwhile thing, for both quality of life reasons and economic reasons,” he said.

The availability of CAR T-cell therapy

Dr Tam pointed out, however, that CAR T-cells for CLL are currently only available on a clinical trial.

“No government anywhere in the world has approved the use of CAR T-cells in CLL.”

Access to this immunotherapy for CLL patients depends on the nature of the trials that are open and what sort of CLL patients those trials are looking to enrol.

“In the past, they have enrolled patients with active CLL who had failed other therapy, and those trials have not resulted in such good outcomes, because these patients, like I said, had poor T-cells anyway, and quite a lot of disease to be treated,” said Dr Tam.

“The newest generation of trials is looking to consolidate an incomplete ibrutinib response, to try and convert someone who has got residual disease on ibrutinib to someone who is MRD negative.

“These trials are moving in the right direction; they’re using CAR T-cells as consolidation and as an earlier line of therapy, not necessarily frontline, but as an earlier line of therapy. I think this is an intelligent way to use this technology.”

Dr Tam said the reason CLL was not an approved indication for CAR T-cell therapy was because it was not yet proven.

“We know using CAR T-cells in just any old-fashioned CLL doesn’t produce such great response rates. They are far lower than in DLBCL and ALL, and cures are probably achieved in less than one in five people with CLL.

“That’s probably because we’re using the CAR T-cells in the wrong way. So, until we’ve proven that the CAR T-cells can be used in a more effective way, in different settings, through clinical trials, the government is not going to approve CAR T-cells for CLL.”

CLL diagnosis and treatment

Dr Tam said CLL was the most common leukaemia in the western world, with about 1000 new cases of CLL diagnosed in Australia each year.

On average half these patients would go on watch and wait and never require treatment in their lifetime. For them the disease doesn’t worsen or cause problems.

“The best thing to do is to just watch very carefully, to get a feel for the pace of the disease for the individual patients, and to wait for a better treatment to come along,” he said.

For those whose disease progresses and needs to be treated, he said access to prognostic panels that helped to define very precisely the subtype of a person’s CLL was important.

“All our patients undergo a FISH¹ study, an IgVH² mutation study, and next-generation sequencing³ to identify gene mutations, so we know which patients are not suitable for chemotherapy.

“These are patients who have p53 deletions and mutations, and we stream those patients towards clinical trials on novel therapies.

“We also know which patients are really suitable for chemotherapy. For example, there is a small subset of patients with a 13q deletion, and more importantly, a mutated IgHV status, that get FCR⁴ chemotherapy and will be cured of CLL in the long-term.

“Then we have a big group of patients where the disease is not curable with chemotherapy but who potentially may respond to chemotherapy; they’re not chemo-resistant but they’re not curable [with this treatment].

“We tend to favour putting these treatment-naïve patients on clinical trials that compare chemotherapy with a combination of novel agents, such as a BTK inhibitor and a BCL-2 inhibitor.

“For patients who have relapsed after chemotherapy, often we’ll put them on either an ibrutinib- based regimen or a venetoclax-based regimen, depending on patient preferences and the logistics of a situation.

“Ibrutinib is very easy to start, but you’re stuck on it pretty much forever, and you have to put up with the low-grade side effects forever, versus venetoclax, which is trickier to start because of tumour lysis⁵ risk, but tends to have a limited duration; in the frontline it’s 12 months, and in the relapsed setting it’s 24 months.

“It’s a question of whether you put in the work right from the start and you’ve got a difficult tumour lysis monitoring period, for a chance at a fixed duration of therapy, or whether you take the easy option, which has got less work to do in the start but treatment needs to be continued indefinitely.”

Dr Tam said CAR T-cell therapy, which is not proven and is just a principle “probably gave the best chance of giving someone a cure in the long term.”

What’s next on the treatment horizon?

Next generation “reversible” BTK inhibitors are coming online and “they are all looking quite active”, said Dr Tam.

“At the moment, all the BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) bond to the same site on the BTK enzyme, so once you get a resistant mutation at the site where the drugs bind, you’re resistant to all the current BTK inhibitors.

“But the next generation drugs, like ARQ-531 and LOXO-305, don’t bind to that site and they bond differently.

“They look quite active in patients who have failed ibrutinib. They’re also looking quite active in themselves, and they might start to come to the frontline or may end up being used ahead of ibrutinib, if the clinical trials show that they are more effective and/or better tolerated than ibrutinib.”

“And there are new versions of venetoclax coming. It’s very hard to improve on this really good class, but we’re now starting to get new drugs within that class that overcome some of the problems with the previous class, and include drugs that are 10 times more potent than venetoclax.

The importance of clinical trial participation

Dr Tam said clinical trials were “very worthwhile” to go on for several reasons.

“From a patient point of view, when you go on a clinical trial, you’re usually seeing an expert who’s got a particular area of interest and these doctors are highly skilled in that particular disease.

“Some are early-phase trials which have a single arm, and others are randomised trials.

“Now in randomised trials, the control arm–the arm we’re comparing against–is chosen carefully as the most active treatment in that disease. So you can be assured when you go on a trial you’re getting the best available treatment anywhere in the world for your disease. Or, you might get a treatment that is even better than standard of care, on the experimental arm.

“So I think, from a selfish point of view, patients get very good medical care when they join clinical trials.

“The other thing about being on a clinical trial is that you are monitored very closely, so you get better than the usual monitoring, as well as access to new drugs that are potentially five to 10 years ahead of the time.”

But there are drawbacks and you have to be prepared to accept uncertainty, Dr Tam said.

“There’s no guarantee that the new drug on the experimental arm is better. The experts think it is, but we do the clinical trial to help us to determine whether that’s true or not.

“And sometimes you have to travel, because all the scans and blood tests need to be done at the hospital where the trial is based. That may be an issue for patients who live in the countryside and where standard therapy may be easier for them.

“The last thing about clinical trials that I often describe to my patients is an altruistic view. It is the “warm and fuzzy” feeling that by helping us do the research, you’re helping advance the cause of medicine in general.

“By participating in a trial, you’re helping us understand the disease better, you’re helping us develop the next generation of treatments, and you may be the reason why the next generation of patients gets even better therapy.

“People on a clinical trial not only get treatment that might benefit them, they were contributing to the body of knowledge that may benefit many generations in the future.”

“All the new exciting treatment we’ve got at the moment, which is doing a better job in controlling leukaemia than we’ve ever done before, with less side effects, have all occurred because previous patients volunteered their time and their trust by going on a clinical trial 10 years ago.

“There are many clinical trials and the most exciting ones are comparing chemotherapy, which is still the frontline standard of care, against combinations of new agents. Hopefully, in five years these will show that new drugs and new drug combinations would do a better job of treating CLL frontline than chemotherapy.

“And that might effectively end chemotherapy as we know it.”

That’s Dr Tam’s holy grail; to develop a permanent natural, meaning nonchemotherapy, solution with treating CLL. To work out a way that the immune system not just controls but is a cure for CLL for all patients.

“That is an achievement I would be extremely proud of. It’s probably 10 years away. I might be out of a job!”

¹ Fluorescence in situ hybridization (FISH) analysis is the single most common cytogenetic abnormality in patients with CLL.

² The immunoglobulin variable region heavy chain (IgVH) gene encodes antibodies that function in the immune response.

³ Next generation sequencing (NGS), massively parallel or deep sequencing, are related terms that describe a DNA sequencing technology which has revolutionised genomic research.

⁴ FCR regimen is a combination of fludarabine, cyclophosphamide, and rituximab .

⁵ Tumour lysis syndrome can occur as a complication during the treatment of cancer, where large amounts of tumour cells are killed off (lysed) at the same time by the treatment, releasing their contents into the bloodstream.