The Importance of Sequencing Monotherapy in CLL

Jacqueline C. Barrientos, MD, MS, Associate Professor, The Feinstein Institute for Medical Research, Northwell Health, Long Island, New York, explains the importance of sequencing monotherapy in chronic lymphocytic leukemia (CLL).

Jacqueline C. Barrientos, MD, MS: In CLL, there's a lot of new agents in the pipeline and in development, and recently approved by the FDA. The goal is always that you have the best chance at a long remission duration and the best outcomes with the best drug regimen.

It is important to know how you're going to select what drug you're going to use. Based on that first therapy, it's how you're going to elect or select the second-line or the third-line therapy. As such, you have to take into consideration a couple of things. One is if the patient is symptomatic.

If it's asymptomatic, you don't treat. As of right now, there's no data to show that it's a good thing to treat a patient that has a diagnosis of CLL -- very different from other malignancies, where you treat immediately after diagnosis. Second important thing to consider is 17p deletion or TP53 mutation.

Both, either or, have very poor outcomes in terms of responses to chemoimmunotherapy regimens, and they also have a very short response duration. Even if you were to receive chemoimmunotherapy, you know that these patients are going to have a shorter remission duration, and they may have a shorter survival.

For these patients, the only therapy right now approved is Ibrutinib. After that, you have to select IgHV mutation status. If you have no 17p deletion but you are mutated, there is a chance, and there's a lot of data that regimens such as FCR could put you in remission for a long period of time. Granted, it comes with a lot of side effects and toxicities.

By NCCN Guidelines right now, these patients also should be getting Ibrutinib, but FCR or BR are some options of care. For people with a mutated IgHV, these patients we know that historically they don't respond as long to chemoimmunotherapy regimen, so Ibrutinib should be the first one.

As of right now associated, NCCN Guidelines recommend Ibrutinib for frontline, for all the patients, regardless of age and commodity cycles. When you relapse, and why do you relapse? The reason why it's so important to know is because it will help you select the next line therapy.

Most patients do stop responding to Ibrutinib because they have to stop the drug because they develop a toxicity. About half of the patients will develop a toxicity that leads to its continuation. The second group of patients, they stop Ibrutinib because they developed a progression of disease, and they are treated differently too.

Last but not least, these patients that develop [inaudible 2:37] transformation, they no longer respond to a drug such as Ibrutinib. If you stop responding to Ibrutinib because you can no longer tolerate the drug, it depends on the toxicity. If you think that the toxicity from the drug is not good, an option of care is Acalabrutinib.

It's a Second-Generation BTK Inhibitor in the NCCN Guidelines, not yet approved. This is off-label use for use in relapsed disease, but it's an option of care for patients that are still responding to a BTK inhibitor but can no longer tolerate it because of toxicities. That's one.

The other option is to change to an alternate kinase inhibitor such as either Idelalisib or Duvelisib, which are PI3K delta inhibitors or to change completely to a Bcl-2 inhibitor when it attacks, which is approved both as monotherapy in patients with 17p, and in combination with Rituximab in all patients with relapsed/refractory disease.

There are some perspective analysis of the data that show that if you were to use chemoimmunotherapy to salvage patients that have no longer responding to Ibrutinib, or Idelalisib, or Venetoclax, chemoimmunotherapy doesn't really work well. Right now, the field of CLL is changing so quickly, that we're no longer using or recommending chemoimmunotherapy approaches, except for a few select patients.

The majority of patients will be treated with a targeted agent. More or less, that's where we are. There's no head-to-head comparison to know which one is better. There are some retrospective analysis presented by Dr. Mato and colleagues from several institutions, that seem to suggest that Venetoclax is better after Ibrutinib discontinuation or Idelalisib discontinuation.

Jeffrey Jones presented the data of a prospective analysis of patients relapsing after Ibrutinib failure or Idelalisib failure, showing anywhere between 60 percent and 70 percent response rate. There's still a couple of patients that don't have a response, even to subsequent lines of therapy.

That's the reason why you always want to get the best drug front-line because there is a chance you might not respond to the next-line therapy.